WO2019057563A1 - Procédé de préparation d'une forme galénique solide comprenant des anticorps par granulation humide, extrusion et sphéronisation - Google Patents

Procédé de préparation d'une forme galénique solide comprenant des anticorps par granulation humide, extrusion et sphéronisation Download PDF

Info

Publication number
WO2019057563A1
WO2019057563A1 PCT/EP2018/074521 EP2018074521W WO2019057563A1 WO 2019057563 A1 WO2019057563 A1 WO 2019057563A1 EP 2018074521 W EP2018074521 W EP 2018074521W WO 2019057563 A1 WO2019057563 A1 WO 2019057563A1
Authority
WO
WIPO (PCT)
Prior art keywords
solid dosage
dosage form
antibody
functional fragment
poly
Prior art date
Application number
PCT/EP2018/074521
Other languages
English (en)
Inventor
Felipe VARUM
Sophie DECOLLOGNY
Roberto BRAVO
Original Assignee
Tillotts Pharma Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tillotts Pharma Ag filed Critical Tillotts Pharma Ag
Priority to KR1020207008146A priority Critical patent/KR20200054984A/ko
Priority to MX2020003031A priority patent/MX2020003031A/es
Priority to CA3075875A priority patent/CA3075875A1/fr
Priority to JP2020515727A priority patent/JP7316268B2/ja
Priority to US16/646,336 priority patent/US20200268675A1/en
Priority to CN201880061124.7A priority patent/CN111107841B/zh
Priority to CN202310130247.4A priority patent/CN116211832A/zh
Priority to EP18768882.5A priority patent/EP3684340A1/fr
Publication of WO2019057563A1 publication Critical patent/WO2019057563A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to a method for preparing immediate and sustained release solid dosage forms, comprising antibodies and functional fragments thereof, by wet granulation, extrusion and spheronization, optionally coated with a delayed release coating, the solid dosage forms prepared by the method and the use of the solid dosage forms in the topical treatment in the gastrointestinal tract of a patient.
  • compositions prepared by various methods comprising biologically active polypeptides like enzymes or hormones.
  • biologically active polypeptides in particular large polypeptides with antigen binding activity such as antibodies and functional fragments thereof, due to their intrinsic nature, are sensitive to any change in their environment, giving rise to inherent instability. Therefore, ensuring their stability and activity as well as the therapeutically efficacious release upon incorporation into a pharmaceutical compositions is very challenging and yet paramount due to the prohibitive costs of such antibodies in quantities that allow their therapeutic application in a patient.
  • this inherent instability of antibodies is independent of whether they are used to prepare a pharmaceutical composition in a liquid, gelatinous, semi-solid, solid or any other form.
  • solid dosage forms many processing steps in the manufacture can be detrimental for stability and activity of an antibody or functional fragment thereof.
  • the use of solid dosage forms is very common for pharmaceutical compositions intended for enteral administration. Enteral administration, and especially oral administration, of solid dosage forms comprising biologically active polypeptides has become increasingly important in recent years, particularly with regards to convenience and safety, as it further allows for the topical treatment of symptoms of diseases of the gastrointestinal tract, as for example inflammatory bowel disease (IBD), colorectal cancer, diarrhea or microbial infections.
  • IBD inflammatory bowel disease
  • colorectal cancer colorectal cancer
  • diarrhea or microbial infections a chronic bowel disease
  • Many factors may affect the chemical and physical stability and thereby the activity of large biologically active polypeptides like antibodies and functional fragments thereof during the incorporation into a solid dosage form. Chemical instability of large polypeptides, e.g.
  • extrusion-spheronization allows for high levels of active components without producing excessively larger particles (in contrast for example to solid dosage forms prepared by direct compression), easy combination of two or more active agents, easy modification of the physical characteristics of the active ingredients and excipients, and particles having high bulk density, low hygroscopicity, high sphericity, narrow particle size distribution and smoother surface (Sahoo et al., J Pharm Res Opin, 9 (2013), pp. 65-68).
  • EP 2 144 599 discloses a composition, comprising a wax-like agent with a melting point between 40 °C and 120 °C, prepared by a an extrusion-spheronization method, where the composition in a last step is heated 15-20 °C above the melting point of the wax-like agent to melt it.
  • EP 0 935 523 discloses a method for embedding and encapsulating an active component in a matrix, comprising plasticizing a matrix material upon heating to form a melt, which needs to be cooled down before an active component can be admixed. The mixture of matrix melt and active component is then extruded and cut or molded into pieces.
  • the recovery of antibodies or functional fragments from solid dosage forms may be further diminished by the use of polymers for a prolonged release of the antibody or functional fragment thereof (i.e. sustained release polymers).
  • polymers for a prolonged release of the antibody or functional fragment thereof i.e. sustained release polymers.
  • IBD like ulcerative colitis or Crohn's disease, for inflamed colonic mucosa to be exposed to an antibody concentration effective for topical treatment, the antibody must retain sufficient stability and activity until it is taken up by the target mucosa.
  • a slow release of antibodies or functional fragments thereof from a solid dosage form is desirable.
  • Gastrointestinal transit in particular, colonic transit of solid dosage forms shows a wide inter- and intra-individual variability (Varum et al., Int. J. Pharm., 2010. 395(1-2): p. 26-36).
  • IBD conditions such as ulcerative colitis or Crohn's disease can also influence transit time. It has been shown that in some cases colonic transit is prolonged in ulcerative colitis, in the areas proximal to the inflamed mucosa. Thus a dosage form will stay in those areas longer, before reaching the inflamed mucosa. If the antibody is not provided in a stable enough form this could mean premature antibody degradation leading to reduced levels of antibody reaching the distal colonic mucosa.
  • a method for preparing a solid dosage form which can be used for the preparation of a multiparticulate solid dosage, by extrusion-spheronization comprising antibodies or functional fragments thereof that minimizes loss of biological activity of the antibody or functional fragment thereof used for the preparation of the solid dosage form.
  • the method should preserve stability and activity of the antibody or functional fragment thereof during individual steps of the preparation, allow release over a short or a prolonged period of time, and reduce interactions of the antibody or functional fragment thereof with other ingredients of the solid dosage form that limits antibody recovery.
  • the present inventors found an advantageous method for preparing a solid dosage form comprising at least one antibody or functional fragment thereof by wet granulation, extrusion and spheronization. This method preserves stability and activity of the antibodies or functional fragments thereof used for the preparation and ensures that an optimal amount of the antibody or functional fragment thereof can be recovered from the solid dosage form upon dissolution.
  • the present invention provides a novel method for preparing a solid dosage form, comprising at least one antibody or functional fragment thereof, prepared by wet granulation, extrusion and spheronization.
  • the present invention relates to the subject matter defined in the following items 1 to 77:
  • a method for preparing a solid dosage form comprising at least one antibody or functional fragment thereof, a surfactant, an extrusion-spheronization aid, a buffer, a disintegrant and at least one further excipient selected from the group consisting of fillers, sustained release agents and combinations thereof, comprising the steps of
  • step b) wet granulating by adding a binding liquid to the powder blend of step a) to obtain a wet mass;
  • step b) extruding the wet mass of step b) and collecting an extrudate
  • step d) spheronizing the extrudate of step c) to obtain wet spheroids
  • the powder blend and/or the binding liquid comprises the at least one antibody or functional fragment thereof, the buffer and the surfactant.
  • the extrusion-spheronization aid is microcrystalline cellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, cyclodextrin, pectin, pectinic acid, starch, dextrins, carrageenan, glycerol monostearate or colloidal silica dioxide, preferably microcrystalline cellulose (e.g., Avicel® PH-101 ).
  • disintegrant is selected from sodium starch glycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, soy polysaccharide and cross-linked alginic acid, preferably sodium starch glycolate.
  • the at least one further excipient is selected from the group consisting of fillers selected from dextrose, lactose, lactose monohydrate, lactose anhydrous, xylitol, mannitol, sucrose, glucose, raffinose, sorbitol, trehalose, dicalcium phosphate, oxides of magnesium or silicon, titanium carbonate, calcium carbonate, magnesium phosphate, porous calcium phosphate or porous magnesium phosphate, amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine and respective salts thereof, propyleneglycol, and polyethylene glycol; and of sustained release agents in the form of sustained release polymers selected from nonionic poly(ethylene oxide) polymers with a molecular weight between 100,000 and 7,000,000, preferably a molecular weight of
  • HPMC 2208 type with a viscosity at 2 wt.-% in water at 20°C between 3 and 100,000 mPa-s such as Methocel K3 Premium LV, Methocel K100 Premium LV, Methocel K4M Premium, Methocel K15 Premium, Methocel K100M Premium
  • mPa-s such as Methocel K3 Premium LV, Methocel K100 Premium LV, Methocel K4M Premium, Methocel K15 Premium, Methocel K100M Premium
  • 2,308 and 9,030 mPa-s e.g. Methocel K4M Premium and Methocel K15M Premium
  • more preferably between about 2,663 and 4,970 mPa-s e.g.
  • Methocel K4M Premium chitosan, xanthan gum, guar gum, tragacanth, locust been gum, acacia gum, carbomers glyceryl (di)behenate (e.g. Compritol® 888 ATO), glyceryl palmitostearate (e.g. Precirol®), and polymethacrylates such as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1 (e.g.
  • Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30D and Eudragit® RS 12.5 poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl meth
  • the solid dosage form is an immediate release solid dosage form
  • the at least one further excipient is a filler selected from the group consisting of dextrose, lactose, lactose monohydrate, lactose anhydrous, mannitol, sorbitol, xylitol, sucrose, glucose, raffinose, trehalose, dicalcium phosphate, oxides of magnesium or silicon, titanium carbonate, calcium carbonate, magnesium phosphate, porous calcium phosphate or porous magnesium phosphate, amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof, propylene glycol, polyethylene glycol, and combinations thereof; preferably dextrose, sucrose, mannitol, sorbitol, xylitol, trehalose, amino acids
  • microcrystalline cellulose as extrusion-spheronization aid
  • sodium starch glycolate as disintegrant
  • sorbitol sucrose, trehalose or mannitol, preferably sorbitol, as filler.
  • the powder blend in step a) comprising i) 20 to 90 %, preferably 30 to 80 %, more preferably 40 to 75%, even more preferably 45 to 70 %, most preferably 45 to 50 % extrusion-spheronization aid;
  • 0.5 to 50 % preferably 0.5 to 40 %, more preferably 1 to 35%, even more preferably 1 to 30 %, even more preferably 1 to 15 %, most preferably about 1 to 10 %, alternatively most preferably 10 to 30 %, of the disintegrant;
  • a filler preferably sucrose, trehalose, sorbitol, mannitol, or amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine and respective salts thereof, and combinations thereof
  • solid dosage form is an immediate release solid dosage form.
  • the powder blend in step a) comprising i) 20 to 70 %, preferably 30 to 60 %, more preferably 40 to 50%, even more preferably about 45 %, extrusion-spheronization aid;
  • a filler preferably sucrose, trehalose, sorbitol, mannitol, or amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof, and combinations thereof
  • a filler preferably sucrose, trehalose, sorbitol, mannitol, or amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof, and combinations thereof
  • solid dosage form is an immediate release solid dosage form.
  • the sustained release coating comprises at least one sustained release polymer selected from the group consisting of polymethacrylates such as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1 (e.g. Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30D and Eudragit® RS 12.5), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2 (e.g.
  • poly(ethylacrylate, methylmethacrylate) 2:1 e.g. Eudragit® NE 30D, Eudragit® NE 40D and Eudragit® NM 30D
  • ethylcellulose e.g. Kollicoat® SR 30D
  • the at least one sustained release agent is a sustained release polymer selected from the group consisting of nonionic poly(ethylene oxide) polymers with a molecular weight between 100,000 and 7,000,000, preferably a molecular weight of about 100,000 (e.g. Polyox® N-10NF); HPMC 2208 type with a viscosity at 2 wt.-% in water at 20°C between 3 and 100,000 mPa-s (such as Methocel K3 Premium LV, Methocel K100 Premium LV, Methocel K4M Premium, Methocel K15 Premium, Methocel K100M Premium), preferably between about 2,308 and 9,030 mPa-s (e.g.
  • Methocel K4M Premium and Methocel K15M Premium are preferably between about 2,663 and 4,970 mPa-s (e.g. Methocel K4M Premium); chitosan; xanthan gum; guar gum; tragacanth; locust been gum; acacia gum; carbomers; glyceryl (di)behenate (e.g. Compritol® 888 ATO); glyceryl palmitostearate (e.g. Precirol®); polymethacrylates such as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1 (e.g.
  • Eudragit® NE 30D Eudragit® NE 40D, Eudragit® NM 30D
  • polyvinyl acetate Kercoat® SR 30D
  • ethylcellulose ethylcellulose
  • combinations thereof preferably, Polyox® N-10NF, Methocel K4M and Compritol® 888 ATO and the like.
  • microcrystalline cellulose as extrusion-spheronization aid
  • solid dosage form is a sustained release solid dosage form.
  • Method according to any of the preceding items comprising at least two further excipients, wherein the first further excipient is a sustained release polymer and the second further excipient is a filler, preferably selected from sorbitol or mannitol, more preferably sorbitol.
  • iii) 1 to 30 %, preferably 1 to 20 %, more preferably 2.5 to 12.5 %, even more preferably 2.5 to 10 %, most preferably about 2.5 to 7.5 %, of the first further excipient comprising at least one sustained release agent;
  • solid dosage form is a sustained release solid dosage form.
  • microcrystalline cellulose as extrusion-spheronization aid
  • sorbitol sucrose, trehalose, mannitol, or amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof, and combinations thereof, preferably sorbitol, as filler.
  • amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof, and combinations thereof, preferably sorbitol, as filler.
  • the powder blend in step a) comprising i) 30 to 85 %, preferably 45 to 80%, more preferably 50 to 80 %, even more preferably about 75 % extrusion-spheronization aid;
  • 0.1 to 40 % preferably 0.5 to 30%, more preferably 1 to 20%, even more preferably 1 to 15 %, most preferably 1 to 10 % of the disintegrant; iii) 1 to 35 %, preferably 1 to 25 %, more preferably 2.5 to 15 %, even more preferably about 2.5 to 10 %, of glyceryl (di)behenate as the first further excipient;
  • solid dosage form is a sustained release solid dosage form.
  • the powder blend in step a) and/or the binding liquid in step b) comprise at least one further additive selected from glidants, plasticizers, antioxidants, stabilizers, humectants, protective colloids, dyes, permeation enhancers, protease inhibitors, and combinations thereof.
  • the solid dosage form comprises an amount of the at least one antibody or functional fragment thereof that allows the administration of a therapeutically effective dose of the at least one antibody or functional fragment thereof as a single unit dose.
  • the solid dosage form comprises from 0.01 to 60 %, preferably from 0.05 to 45 %, more preferably from 0.1 to 30 %, even more preferably from 0.5 to 25 %, even more preferably from 1 to 20 %, even more preferably from 1 to 15 %, most preferably 5 to 15 %, of the at least one antibody or functional fragment thereof, relative to the total weight of the solid dosage form.
  • the functional antibody fragment is a Fab fragment, a F(ab')2 fragment, a Fab' fragment, an scFv, a dsFv, a VHH, a diabody, a triabody, a tetrabody, an Fc fusion protein or a minibody.
  • the at least one antibody or functional fragment thereof is selected from antibodies specific to tumor necrosis factor alpha (TNFa) and functional fragments thereof, antibodies specific to ⁇ 4 ⁇ 7 integrin and functional fragments thereof, antibodies specific to CD3, CD4 or CD20 and functional fragments thereof, antibodies specific to interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 23 (IL-23) or to their receptors and functional fragments thereof, antibodies specific to CXCL10/IP-10 and functional fragments thereof, and antibodies specific to p40 protein subunit and functional fragments thereof.
  • TNFa tumor necrosis factor alpha
  • IL-6 interleukin 6
  • IL-12 interleukin 12
  • IL-13 interleukin 13
  • IL-23 interleukin 23
  • a gastrointestinal disease preferably an inflammatory bowel disease (IBD), celiac disease, a gastrointestinal infection, colorectal cancer or small intestine cancer, more preferably an IBD like Crohn's disease or ulcerative colitis.
  • IBD inflammatory bowel disease
  • celiac disease a gastrointestinal infection
  • colorectal cancer a gastrointestinal infection
  • colorectal cancer a gastrointestinal infection
  • small intestine cancer more preferably an IBD like Crohn's disease or ulcerative colitis.
  • the at least one antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, visilizumab, eldelumab, abrilumab, canakinumab, tocilizumab, ustekinumab, natalizumab, etrolizumab, priliximab, vedolizumab and functional fragments thereof; from anti-TNFa antibodies or functional fragments thereof with light chain variable domains and/or heavy chain variable domains comprising complementarity-determining regions (CDRs) with amino acid sequences as disclosed in claim 2 of PCT/EP2017/056218, in claim 2 of PCT/EP2017/056246, in claim 2 of PCT/EP2017/056237 and/or in claim 2 of PCT/EP2017/056227, as originally filed; from anti-TNFa antibodies or functional fragments
  • Method according to item 27, wherein the antibody specific to TNFa or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol and golimumab and functional fragments thereof; from anti-TNFa antibodies or functional fragments thereof with light chain variable domains and/or heavy chain variable domains comprising complementarity-determining regions (CDRs) with amino acid sequences as disclosed in claim 2 of PCT/EP2017/056218, in claim 2 of PCT/EP2017/056246, in claim 2 of PCT/EP2017/056237 and/or in claim 2 of PCT/EP2017/056227, as originally filed; from anti- TNFa antibodies or functional fragments thereof comprising a heavy chain variable domain amino acid sequence and/or a light chain variable domain amino acid sequence according to claim 4 of PCT/EP2017/056218, claims 5 and 6 of PCT/EP2017/056246, claims 5 and 6 of PCT/EP2017/056237, and
  • the at least one antibody or functional fragment thereof is comprised in the binding liquid in a concentration (w/v) of 0.01 to 1000 mg/ml, preferably 0.1 to 500 mg/ml, more preferably 0.1 to 200 mg/ml, even more preferably 0.1 to 100 mg/ml, even more preferably 1 to 100 mg/ml, even more preferably 5 to 100 mg/ml, even more preferably 10 to 50 mg/ml.
  • the binding liquid is an aqueous solution.
  • the amount of surfactant relative to the total volume of the binding liquid (w/v) is from 0.005 to 2.0 %, preferably 0.01 to 1 %, more preferably 0.05 to 0.8 %, even more preferably 0.05 to 0.5 %, even more preferably 0.1 to 0.5, most preferably about 0.1 % based on the total volume of the binding liquid; or wherein the concentration (w/w) of the surfactant in the solid dosage form is from 0.001 to 1 %, preferably from 0.005 to 0.5 %, more preferably from 0.01 to 0.5 %, even more preferably from 0.01 % to 0.25 %, based on the total weight of the solid dosage form after step e).
  • the surfactant is selected from the group consisting of polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81 , polysorbate 85, poloxamer 124, poloxamer 181 , poloxamer 188, poloxamer 237, poloxamer 331 , poloxamer 338 and poloxamer 407, glyceryl monostearate, polyethoxylated castor oil, PEG-40 hydrogenated castor oil, macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate, caprylocaproyl macrogol-8 glyceride, D-a- tocopherol polyethylene glycol 1000 succinate, glyceryl monostearate, lecithin, sorbitan monopalmitate, cetyl alcohol, oleyl alcohol, sodium glycolate, sodium de(s)oxycholate, polyethylene glycol, polypropylene glycol,
  • binding liquid comprises the surfactant
  • the buffer comprised in the powder blend and/or the binding liquid is selected from acetate, citrate, histidine, hydroxymethylaminomethane (TRIS), and phosphate buffers (buffer salts), and combinations thereof.
  • step a) or the binding liquid of step b) further comprises a binder, preferably selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone and combinations thereof.
  • a binder preferably selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone and combinations thereof.
  • step e) Method according to any of the preceding items, wherein during step e) the drying of the wet spheroids is carried out at a temperature lower than 55 °C, preferably lower than 50 °C, more preferably lower than 45 °C, even more preferably at about 40 °C.
  • step e) Method according to item 39, wherein during step e) the drying of the wet spheroids is carried out at a temperature lower than 45 °C using vacuum-assisted drying.
  • the residual solvent content (i.e. residual moisture level) of the solid dosage form is less than 15 wt.-%, preferably less than 10 wt.-%, more preferably less than 8 wt.-%, even more preferably less than 5 wt.-%, even more preferably less than 3 wt.-%, even more preferably less than 2 %, relative to the total weight of the solid dosage form.
  • the delayed release coating comprises at least one component selected from coating materials that disintegrate pH-dependently, coating materials that disintegrate time-dependently, coating materials that disintegrate due to enzymatic triggers in the intestinal environment, and combinations thereof.
  • the coating materials that disintegrate pH-dependently are selected from poly vinyl acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate HP-50, HP-55 or HP-55S, cellulose acetate phthalate, acrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(methacrylic acid, ethyl acrylate) 1 :1 (Eudragit® L100-55,
  • Eudragit® L30D-55 poly(methacrylic acid, methyl methacrylate) 1 :1 (Eudragit® L-100, Eudragit® L12.5), poly(methacrylic acid, methyl methacrylate) 1 :2 (Eudragit® S-100, Eudragit® S12,5, Eudragit® FS30D), and combinations thereof;
  • the coating materials that disintegrate time-dependently are selected from polymethacrylates such as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2 (e.g.
  • Eudragit® RL 30D Eudragit® RL100, Eudragit® RL PO, and Eudragit® RL 12.5
  • Eudragit® RS 30D Eudragit® RS 100, Eudragit® RS PO, and Eudragit® RS 12.5
  • poly(ethylacrylate, methylmethacrylate) 2:1 e.g. Eudragit® NE 30D, Eudragit® NE 40D, Eudragit® NM 30D
  • Polyvinyl acetate Kollicoat SR 30D
  • the coating materials that disintegrate due to enzymatic triggers in the intestinal environment are selected from chondroitin sulfate, pectin, guar gum, chitosan, Inulin, lactulose, raffinose, stachyose, alginate, dextran, xanthan gum, locust bean gum, arabinogalactan, amylose, amylopectin, pullulan, carrageenan, cyclodextrin, scleroglucan, chitin, curdulan, levan, starch, resistant starch, azo compounds being degraded by azo bonds splitting bacteria, and combinations thereof.
  • the delayed release coating comprises a combination of at least one coating material that disintegrates pH-dependently and at least one coating material that disintegrates due to enzymatic triggers in the intestinal environment.
  • the delayed release coating comprises a combination of at least one enteric polymer, preferably poly(methacrylic acid, methyl methacrylate) 1 :2, and at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch, and combinations thereof, preferably and resistant starch.
  • enteric polymer preferably poly(methacrylic acid, methyl methacrylate) 1 :2
  • at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin,
  • the delayed release coating comprises i) an inner coating comprising partially neutralized enteric polymer adjusted to pH 8, preferably partially neutralized poly(methacrylic acid, methyl methacrylate) 1 :2 adjusted to pH 8, and containing a buffer salt, and ii) an outer coating comprising a combination of at least one enteric polymer, preferably poly(methacrylic acid, methyl methacrylate) 1 :2, and at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch, and combinations thereof, preferably resistant starch.
  • the at least one component e.g. the combination of the at least one enteric polymer, preferably poly(methacrylic acid, methyl methacrylate) 1 :2, and the at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch, and combinations thereof, preferably resistant starch, is dispersed in an organic solvent, a mixture of organic solvents or a mixture of at least one organic solvent and water, which is applied to the particles preferably by spray coating, more preferably fluidized-bed spray coating.
  • the at least one component e.g. the combination of the at least one enteric polymer, preferably poly(methacrylic acid, methyl methacrylate) 1 :2, and the at least one polysaccharide selected from
  • Method according item 49 wherein the combination is dispersed in a mixture of at least one organic solvent and water, prepared by mixing a enteric polymer dissolved in an organic solvent with an aqueous re-dispersion of the at least one polysaccharide.
  • Method according to any one of items 43 to 51 comprising a delayed release coating for targeted release of the antibody or functional fragment thereof starting in the ileum, the terminal ileum, the ileocolonic region, the ascending colon, transverse colon or the descending colon.
  • the solid dosage form is an immediate release dosage form, allowing the recovery of at least 80 %, preferably at least 85 %, more preferably at least 90 %, even more preferably at least 93 %, even more preferably at least 95 %, even more preferably at least 97 %, even more preferably at least 98%, of the at least one antibody or functional fragment thereof from the solid dosage form within 2 h, preferably within 1 h, of continuously immersing the solid dosage form in an aqueous buffer solution under constant movement.
  • the solid dosage form is a sustained release dosage form, allowing the recovery of at least 45 %, preferably at least 55%, more preferably at least 65 %, even more preferably at least 75 %, even more preferably at least 80 %, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 93%, even more preferably at least 95 %, even more preferably at least 97 %, even more preferably at least 98 %, of the at least one antibody or functional fragment thereof from the solid dosage form within 4 h, or 6 h, or 8 h, or 10 h, or 12 h, or 14 h, or 16 h, or 18 h, or 20 h, or 22 h, or 24 h, or 26 h, or 28 h, or 30 h, 32 h, etc., of continuously immersing the solid dosage form in an aqueous buffer solution under constant movement.
  • the solid dosage form is a sustained release dosage form, allowing a sustained release of the at least one antibody or functional fragment thereof over a time period of at least 5 h, preferably at least 10 h, more preferably at least 12 h, even more preferably at least 20 h, most preferably at least 24 h, upon continuously immersing the solid dosage form in an aqueous buffer solution under constant movement.
  • Solid dosage form comprising a therapeutically effective dose of at least one antibody or functional fragment thereof, an extrusion-spheronization aid, a surfactant, a buffer, a disintegrant, at least one further excipient selected from the group consisting of fillers, sustained release agents and combinations thereof, and optionally at least one further additive, which is obtainable by the steps of dry mixing, wet granulation, extrusion, spheronization and drying.
  • Solid dosage form according to item 60 obtainable by the method comprising the steps of dry mixing, wet granulation, extrusion, spheronization and drying as defined in any one of items 1 to 58.
  • Solid dosage form according to any one of items 59 to 63 for use in the topical treatment in the ileum, the terminal ileum, the ileocolonic region, the ascending colon, transverse colon or the descending colon of a patient.
  • Multiparticulate drug delivery system comprising multiple solid dosage form units, each of the solid dosage form unit obtainable by the method of any one of items 1 to 58, wherein the multiparticulate drug delivery system preferably is a sachet, stickpack, drinking straw (Xstraw®), capsule or tablet.
  • a multiparticulate drug delivery system comprising a plurality of solid dosage form units, each solid dosage form unit comprising at least one antibody or functional fragment thereof, a surfactant, an extrusion-spheronization aid, a buffer, a disintegrant and at least one further excipient selected from the group consisting of fillers, sustained release agents and combinations thereof, and preferably each solid dosage form unit having a predetermined axis and the same predetermined cross-sectional profile, wherein at least 80% by number of those solid dosage form units, preferably 90%, more preferably 95%, have a median aspect ratio between 0.7 and 1 .7, the aspect ratio being defined as solid dosage form unit length along the predetermined axis divided by the smallest cross-sectional dimension.
  • a multiparticulate drug delivery system according to item 66, wherein the median aspect ratio is above 0.8, preferably above 0.9, and below 1 .6, preferably below 1 .5, more preferably 1 .4, even more preferably below 1.3, even more preferably below 1 .2, most preferably about 1 .
  • Multiparticulate drug delivery system according to item 66 or 67, wherein the solid dosage form units have a span of aspect ratio of less than 0.9, preferably less than 0.8, more preferably less than 0.7, even more preferably less than 0.6, most preferably less than 0.5.
  • Multiparticulate drug delivery system according to any of items 66 to 68, allowing the recovery of at least 80 %, preferably at least 85%, more preferably at least 93 %, even more preferably at least 95 %, even more preferably at least 97%, even more preferably at least 98%, of the at least one antibody or functional fragment thereof from the solid dosage form units.
  • Multiparticulate drug delivery system according to any of items 66 to 69, allowing the recovery of at least 80 %, preferably at least 85%, more preferably at least 93 %, even more preferably at least 95 %, even more preferably at least 97%, even more preferably at least 98%, of the at least one antibody or functional fragment thereof from the solid dosage form units within 30 min, or 1 h, or 2 h, of continuously immersing the solid dosage form in an aqueous buffer solution under constant movement (immediate release).
  • Multiparticulate drug delivery system according to any of items 66 to 70, allowing the recovery of at least 80 %, preferably at least 85%, more preferably at least 93 %, even more preferably at least 95 %, even more preferably at least 97%, even more preferably at least 98%, of the at least one antibody or functional fragment thereof from the solid dosage form units, within 4 h, or 6 h, or 8 h, or 10 h, or 12 h, or 14 h, or 16 h, or 18 h, or 20 h, or 22 h, or 24 h, or 26 h, or 28 h, or 30 h, or 32 h, or 34 h, or 36 h, etc., of continuously immersing the solid dosage form in an aqueous buffer solution under constant movement (sustained release).
  • Multiparticulate drug delivery system according to any of items 66 to 71 , wherein the solid dosage form units are prepared by extrusion-spheronization.
  • Multiparticulate drug delivery system according to any of items 66 to 72, wherein the solid dosage form units are prepared by extrusion-spheronization according to the method of any of any one of items 1 to 58.
  • Multiparticulate drug delivery system according to any of items 66 to 72, wherein the solid dosage form units are prepared by extrusion, and are non-spheronized solid dosage form units.
  • Multiparticulate drug delivery system according to any of items 66 to 74, wherein the multiparticulate drug delivery system is prepared from multiple solid dosage form units by compression, encapsulation or extrusion-spheronization.
  • Multiparticulate drug delivery system according to any of items 66 to 75, wherein the multiparticulate drug delivery system or the individual solid dosage form units comprise a delayed release coating, which is applied as a further coating.
  • a solid dosage form consisting of a single solid dosage form unit of the solid dosage form units comprised in the multparticulate drug delivery system according to any one of items 65 to 76.
  • Figure 1 (A) Adalimumab recovery in citrate-TRIS buffer pH 7, (B) aggregation profile and (C) fragmentation profile of adalimumab after individual steps during the preparation of Comparative Example 1 pellets by wet granulation, extrusion, spheronization and drying in comparison to a 1 .0 mg/ml adalimumab standard, determined 30 min, 60 min or 24 h after each step. Adalimumab quantification was determined calorimetrically by total protein content analysis using Bradford reagent.
  • FIG. 2 Adalimumab release from pellets prepared with different concentrations of Tween® 20 or Kolliphor® 188 in the adalimumab containing binding liquid used for granulation.
  • the excipients were the same as used in Comparative Example 2 pellets, except Example 1 and Comparative Example 3, which contained mannitol instead of sorbitol.
  • Pellets dissolved in citrate-TRIS buffer pH 7. Total protein content on dissolution samples was determined colorimetrically using Bradford reagent. Results are expressed as mean of 3 replicates with corresponding standard deviations.
  • Figure 3 Size exclusion chromatography (aggregates) data from adalimumab recovered after 24 h from Example 1 , Example 2 and Example 3 pellets (immediate release) in citrate- TRIS buffer pH 7. Samples were prepared in triplicates and compared to a positive control of 1 .0 mg/ml adalimumab in the same buffer.
  • FIG. 4 Microchip electrophoresis (fragments) data from adalimumab recovered after 24 h from Example 1 , Example 2 and Example 3 pellets in citrate-TRIS buffer pH 7. Samples were prepared in triplicates and compared to a positive control of 1 .0 mg/ml adalimumab in the same buffer.
  • FIG. 5 Adalimumab release in citrate-TRIS buffer pH 7.0 from Example 4, Example 5, Example 6 and Example 7 pellets. Results are expressed as mean of 3 replicates with corresponding standard deviations.
  • FIG. 6 (A) Adalimumab release in citrate-TRIS buffer pH 7.0 of different sustained release pellets. Results are expressed as mean of 3 replicates with correspondent standard deviation. (B) Dissolution in citrate TRIS buffer pH 7 of different sustained release pellets comprising Compritol® ATO 188 as sustained release polymer.
  • Figure 7 Adalimumab release from immediate release pellets prepared by adding adalimumab directly into the powder blend and using different Tween® 20 concentrations (0.1 % Tween® 20 (Comparative Example 4), 0.25% Tween® 20 (Example 15) and 0.5% Tween® 20 (Example 16) in the binding liquid.
  • FIG 8 Adalimumab release from Immediate release adalimumab loaded pellets (Comparative Example 5), prepared by extrusion-spheronization, were further coated in a fluid bed equipment with a sustained release coating comprising Eudragit® RS 30D, triethyl citrate as plasticizer and Syloid ® 244FP as anti-tacking to a polymer weight gain of 28.5% (Example 17), 20.6% (Example 18) and 13.7% (Example 19). Additionally, no significant increase in adalimumab aggregates or fragments was observed in Example 19 pellet samples collected after 24h in dissolution, as determined by size exclusion chromatography and microchip electrophoresis, respectively (Figure 8B),
  • the present invention relates to a method for preparing a solid dosage form comprising at least one antibody or functional fragment thereof, a surfactant, an extrusion-spheronization aid, a buffer, a disintegrant and at least one further excipient selected from the group consisting of fillers, sustained release agents and combinations thereof.
  • the inventive method comprises the steps of a) providing a powder blend comprising the extrusion-spheronization aid, the disintegrant, and the at least one further excipient; b) wet granulating by adding a binding liquid to the powder blend of step a) to obtain a wet mass; c) extruding the wet mass of step b) and collecting an extrudate; d) spheronizing the extrudate of step c) to obtain wet spheroids; and e) drying the wet spheroids to obtain the final solid dosage form; wherein the powder blend and/or the binding liquid comprises the at least one antibody or functional fragment thereof, the buffer and the surfactant.
  • solid dosage form as used herein may be understood to be equivalent to "solid pharmaceutical dosage form” or "pharmaceutical composition formulated into a solid dosage form” and includes for example pellets, capsules, granules, mini tablets and such.
  • the solid dosage form is a pellet, mini sphere, bead, granule or mini tablet.
  • the solid dosage form is a pellet.
  • Multiple unit solid dosage forms of the present invention may be combined into a single-unit formulation, for example in the form of a tablet, hard gelatin/HPMC capsule, sachet stickpack, drinking straw (Xstraw®), caplet, or pill.
  • antibody in the context of the present invention, refers to "immunoglobulin" (Ig), which is defined as a protein belonging to the class IgG, IgM, IgE, IgA, or IgD (or any subclass thereof), and includes all conventionally known antibodies and functional fragments thereof.
  • a "functional fragment" of an antibody/immunoglobulin is defined as antigen-binding fragment or other derivative of a parental antibody that essentially maintains the properties of such a parental antibody.
  • An "antigen-binding fragment” of an antibody/immunoglobulin is defined as a fragment (e.g., a variable region of an IgG) that retains the antigen-binding region.
  • an “antigen-binding region" of an antibody typically is found in one or more hypervariable region(s) of an antibody, i.e., the CDR-1 , -2, and/or -3 regions.
  • Antigen-binding fragments according to the invention include the domain of a F(ab')2 fragment and a Fab fragment.
  • Fusional fragments include Fab fragment, F(ab')2 fragment, Fab' fragment, scFv, dsFv, VHH, diabody, triabody, tetrabody, Fc fusion protein and minibody.
  • the F(ab')2 or Fab domain may be engineered to minimize or completely remove the intermolecular disulphide interactions that occur between the CH1 and CL domains.
  • the antibodies or functional fragments used for the present invention may be part of bi- or multifunctional constructs.
  • Fab fragments can be obtained as the purified digestion products after digestion of an antibody with a cysteine proteinase like papain (EC 3.4.22.2).
  • F(ab')2 fragments can be obtained as the purified digestion products after digestion of an antibody with pepsin (EC 3.4.23.1 ) or IdeS (Immunoglobulin degrading enzyme from Streptococcus pyogenes; EC 3.4.22).
  • Fab' fragments can be obtained from F(ab')2 fragments in mild reducing conditions, whereby each F(ab')2 molecule gives rise to two Fab' fragments.
  • An scFv is a single chain Fv fragment in which the variable light (“VL”) and variable heavy (“VH”) domains are linked by a peptide bridge.
  • a “diabody” is a dimer consisting of two fragments, each having variable regions joined together via a linker or the like (hereinafter referred to as diabody-forming fragments), and typically contain two Vi_s and two VHS.
  • Diabody-forming fragments include those consisting of VL and VH, VL and VL, VH and VH, etc., preferably VH and VL.
  • the linker joining variable regions is not specifically limited, but preferably short enough to avoid noncovalent bonds between variable regions in the same fragment. The length of such a linker can be determined as appropriate by those skilled in the art, but typically 2-14 amino acids, preferably 3-9 amino acids, especially 4-6 amino acids are used.
  • the VL and VH encoded on the same fragment are joined via a linker short enough to avoid noncovalent bonds between the VL and VH on the same chain and to avoid the formation of single-chain variable region fragments so that dimers with another fragment can be formed.
  • the dimers can be formed via either covalent or noncovalent bonds or both between diabody-forming fragments.
  • diabody-forming fragments can be joined via a linker or the like to form single- chain diabodies (sc(Fv)2). By joining diabody-forming fragments using a long linker of about 15-20 amino acids, noncovalent bonds can be formed between diabody-forming fragments existing on the same chain to form dimers.
  • polymerized antibodies such as trimers or tetramers can also be prepared by joining three or more diabody-forming fragments.
  • the functional fragment in the solid dosage form prepared by the inventive method is a Fab fragment, a F(ab')2 fragment, a Fab' fragment, an scFv, a dsFv, a VHH, a diabody, a triabody, a tetrabody, an Fc fusion protein or a minibody.
  • Preferred functional fragments used in the present invention are Fab fragments, F(ab')2 fragments, Fab' fragments, scFv and diabodies.
  • the antibody or functional fragment thereof used in the inventive method for the preparation of the solid dosage form is not particularly limited.
  • the antibody or functional fragment thereof is an antibody.
  • the antibody or functional fragment thereof is functional fragment as defined above.
  • the antibody or functional fragment thereof may further comprise one or more modifications, e.g. in the form of added or substituted residues, that improve stability, specificity or targeting. These may include any such modifications that are known in the art.
  • the antigen against which the antibody or functional fragment is directed i.e. the immunogen, peptide, protein, or other molecular structure to which the antibody or functional fragment thereof can specifically bind, is not limited.
  • “specific to” or “specific binding” refers to the ability of the antibody or functional fragment thereof to discriminate between the target of interest and an unrelated biomolecule (e.g. for antibodies specific to human TNFa to discriminate between human TNFa and an unrelated biomolecule), as determined, for example, in accordance with specificity assay methods known in the art. Such methods comprise, but are not limited to, Western blots and enzyme-linked immunosorbent assay (ELISA) tests.
  • ELISA enzyme-linked immunosorbent assay
  • the antibody or functional fragment thereof is suitable for use in the treatment of a gastrointestinal disease, for example an inflammatory bowel disease (IBD) (e.g. Crohn's disease or ulcerative colitis), cancer (e.g. colorectal cancer or small intestine cancer), celiac disease, or an infections (e.g. Clostridium difficile infection), more preferably an IBD.
  • IBD inflammatory bowel disease
  • cancer e.g. colorectal cancer or small intestine cancer
  • celiac disease e.g. Clostridium difficile infection
  • the antibody or functional fragment thereof is suitable for use in the topical treatment in the jejunum, ileum or large intestine of the gastrointestinal tract of a patient.
  • the antibody or functional fragment thereof is selected from antibodies specific to tumor necrosis factor alpha (TNFa) and functional fragments thereof, antibodies specific to ⁇ 4 ⁇ 7 integrin and functional fragments thereof, antibodies specific to CD3, CD4 or CD20 and functional fragments thereof, antibodies specific to interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 23 (IL- 23) or to their receptors and functional fragments thereof, antibodies specific to CXCL10/IP- 10 and functional fragments thereof, and antibodies specific to p40 protein subunit and functional fragments thereof.
  • TNFa tumor necrosis factor alpha
  • IL-6 interleukin 6
  • IL-12 interleukin 12
  • IL-13 interleukin 13
  • IL- 23 interleukin 23
  • the antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, visilizumab, eldelumab, abrilumab, canakinumab, tocilizumab, ustekinumab, natalizumab, etrolizumab, priliximab, vedolizumab and functional fragments thereof.
  • the antibody or functional fragment thereof in the solid dosage form prepared by the inventive method specifically binds to TNFa.
  • anti-TNFa antibody refers to the ability of the antibody or fragment to discriminate between human TNFa and human TNF3.
  • TNFa antibody or functional fragment thereof is a TNFa antibody.
  • TNFa antibody or functional fragment thereof is a functional fragment of a TNFa antibody.
  • 5,919,452 discloses anti-TNFa chimeric antibodies and their use in treating pathologies associated with the presence of TNFa. Further anti-TNFa antibodies are disclosed in Stephens et al. (Immunology, 85, 668-674, 1995), GB-A-2 246 570, GB-A-2 297 145, US 8,673,310, US 2014/0193400, EP 2 390 267 B1 , US 8,293,235, US 8,697,074, WO 2009/155723 A2 and WO 2006/131013 A2.
  • infliximab a chimeric IgG anti- human monoclonal antibody (Remicade®); (ii) etanercept, a TNFR2 dimeric fusion protein, with an lgG1 Fc (Enbrel®); (iii) adalimumab, a fully human monoclonal antibody (mAb) (Humira®), (iv) certolizumab, a PEGylated Fab fragment (Cimzia®) and (v) golimumab, a human IgGIK monoclonal antibody (Simponi®). Moreover, various biosimilars are in development.
  • the antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol and golimumab or functional fragments thereof.
  • the at least one antibody or functional fragment thereof is selected from anti-TNFa antibody or functional fragment thereof as disclosed in PCT applications PCT/EP2017/056218, PCT/EP2017/056246, PCT/EP2017/056237 and PCT/EP2017/056227, as originally filed.
  • the at least one antibody or functional fragment thereof is an anti-TNFa antibody or functional fragment thereof with a light chain variable domain and/or a heavy chain variable domain comprising complementarity-determining regions (CDRs) with amino acid sequences as disclosed in PCT applications PCT/EP2017/056218, PCT/EP2017/056246, PCT/EP2017/056237 and PCT/EP2017/056227, as originally filed.
  • CDRs complementarity-determining regions
  • the at least one antibody or functional fragment thereof is selected from anti-TNFa antibodies or functional fragments thereof with a light chain variable domain and/or a heavy chain variable domain comprising one or more CDRs with amino acid sequences as disclosed in SEQ ID NO:7, 9, 12, 14, 24 and 25 of PCT/EP2017/056218, in SEQ ID NO:7-1 1 and 6 of PCT/EP2017/056246, in SEQ ID NO:7-12 of PCT/EP2017/056237, in SEQ ID NO:1 -4, 7 and 6 of PCT/EP2017/056227, and combinations thereof.
  • the at least one antibody or functional fragment thereof is selected from anti-TNFa antibodies or functional fragments thereof with a light chain variable domain and a heavy chain variable domain comprising CDRs with amino acid sequences as disclosed in claim 2 of PCT/EP2017/056218, in claim 2 of PCT/EP2017/056246, in claim 2 of PCT/EP2017/056237 and/or in claim 2 PCT/EP2017/056227, as originally filed.
  • the at least one anti-TNFa antibody or functional fragment thereof is selected from the group consisting of anti-TNFa antibodies or functional fragments thereof comprising a heavy chain variable domain amino acid sequence and/or a light chain variable domain amino acid sequence according to claim 4 of PCT/EP2017/056218, claims 5 and 6 of PCT/EP2017/056246, claims 5 and 6 of PCT/EP2017/056237, claim 4 of PCT/EP2017/056227, and combinations thereof.
  • the solid dosage form prepared by the method of the present invention comprises one or more surfactants.
  • surfactant refers to a surface-active substance, i.e. a substance that reduces the surface tension of a fluid in which it is dissolved and/or reduces the interfacial tension between oil and water.
  • surfactants can be e.g.
  • non-ionic surfactants that can be included in the solid dosage form prepared by the method of the present invention include but are not limited to polysorbates such as polysorbates 20, 28, 40, 60, 65, 80, 81 and 85; poloxamers such as poloxamers 124, 181 , 188, 237, 331 , 338 and 407; or polyethylene- polypropylene glycol; alkyl poly(ethylene oxide), alkyl polyglucosides (e.g., octyl glucoside and decyl maltoside); fatty alcohols such as cetyl alcohol and oleyl alcohol; glyceryl monostearate, lecithin, sorbitan monopalmitate, sodium glycolate, sodium de(s)oxycholate, polyethoxylated castor oil (Kolliphor® EL), PEG-40 hydrogenated castor oil (Cremophor® RH40), macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate, polyoxyl 15 hydroxyste
  • the surfactant is selected from the group consisting of polysorbate 20 (Tween® 20), polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81 , polysorbate 85, poloxamer 124, poloxamer 181 , poloxamer 188 (Kolliphor® 188), poloxamer 237, poloxamer 331 , poloxamer 338 and poloxamer 407, glyceryl monostearate, polyethoxylated castor oil (Kolliphor® EL), PEG-40 hydrogenated castor oil (Cremophor® RH40), macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate (Kolliphor® HS 15), caprylocaproyl macrogol-8 glyceride (Labrasol®), D-a-Tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), glyceryl monostearate, lecithin,
  • the surfactant is selected from the group consisting of polysorbate 20 (Tween® 20), polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81 , polysorbate 85, poloxamer 124, poloxamer 181 , poloxamer 188 (Kolliphor® 188), poloxamer 237, poloxamer 331 , poloxamer 338 and poloxamer 407, glyceryl monostearate, polyethoxylated castor oil (Kolliphor® EL), PEG-40 hydrogenated castor oil (Cremophor® RH40), macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate (Kolliphor® HS 15), caprylocaproyl macrogol-8 glyceride (Labrasol®), D-a-Tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), glyceryl monostearate.
  • polysorbate 20 Teween® 20
  • the surfactant is selected from polysorbate 20 or poloxamer 188, preferably polysorbate 20.
  • the amount of surfactant to be used is not particularly limited. In one embodiment of the present invention, the amount of surfactant used relative to the total volume of the binding liquid (w/v) is from 0.005 to 2.0 %, preferably 0.01 to 1 %, more preferably 0.05 to 0.8 %, even more preferably 0.05 to 0.5 %, even more preferably 0.1 to 0.5, most preferably about 0.1 %.
  • total volume of the binding liquid refers to the total volume of binding liquid added during step b) of the inventive method.
  • the amount of surfactant relative to the total volume of the binding liquid (w/v) may be about 0.03 %, about 0.05 %, about 0.08 %, about 0.1 %, about 0.15 %, about 0.2 %, about 0.25 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.6 %, about 0.7 %, or about 0.8 %.
  • the concentration (w/w) of the surfactant in the solid dosage form is from 0.001 to 1 %, preferably from 0.005 to 0.8 %, more preferably from 0.005 to 0.5 %, even more preferably 0.01 % to 0.25 %, based on the total weight of the solid dosage form after step e).
  • the concentration (w/w) of the surfactant in the solid dosage form depends on the concentration (w/w) of the at least one antibody or functional fragment thereof, such that for a higher concentration of the at least one antibody or functional fragment thereof a higher concentration of surfactant may be used.
  • extrusion-spheronization aid used in the inventive method for the preparation of the solid dosage form is not particularly limited.
  • extrusion-spheronization aids that can be used for the present invention include microcrystalline cellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, cyclodextrin, pectin, pectinic acid, starch, dextrins, carrageenan, glycerol monostearate, colloidal silica dioxide.
  • the extrusion-spheronization aid is microcrystalline cellulose (e.g. Avicel® PH-101 ).
  • the disintegrant in the solid dosage form prepared by the method of the present invention is not particularly limited.
  • the disintegrant include sodium starch glycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, soy polysaccharide or cross-linked alginic acid.
  • the disintegrant is sodium starch glycolate (e.g. Explotab®).
  • the solid dosage form prepared by the inventive method further comprises a buffer (buffer salt).
  • buffers are known in the art. Suitable buffers may be one or more buffers/buffer salts, for example be selected from acetate, citrate, histidine, hydroxymethylaminomethane (TRIS), and phosphate buffers, and the like.
  • the buffer in the solid dosage form prepared by the inventive method is selected from the group consisting of acetate, citrate, TRIS, histidine and phosphate buffers, and combinations thereof.
  • the buffer may be comprised in the binding liquid or may be comprised in the powder blend.
  • the buffer is comprised in the binding liquid if the at least one antibody or functional fragment thereof is comprised in the binding liquid, and is comprised in the powder blend if the at least one antibody or functional fragment thereof is comprised in the powder blend.
  • the at least one further excipient selected from the group consisting of fillers, sustained release agents and combinations thereof in the solid dosage form prepared by the method of the present invention is not particularly limited.
  • fillers examples include dextrose, lactose, lactose monohydrate, lactose anhydrous, mannitol, sorbitol, xylitol,(pregelatinized) starch, sucrose, glucose, raffinose, trehalose, dicalcium phosphate, oxides of magnesium or silicon, titanium carbonate, calcium carbonate, magnesium phosphate, porous calcium phosphate or porous magnesium phosphate, propyleneglycol and polyethylene glycol.
  • fillers are amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and salts thereof.
  • Sustained release agents are preferably selected from the group of sustained release polymers.
  • sustained release polymers include nonionic poly(ethylene oxide) polymers with a molecular weight between 100,000 and 7,000,000, preferably a molecular weight of about 100,000 (e.g.
  • Polyox® N-10NF from Dows Chemicals HPMC 2208 type with a viscosity at 2 wt.-% in water at 20°C between 3 and 100000 mPa-s (such as Methocel K3 Premium LV, Methocel K100 Premium LV, Methocel K4M Premium, Methocel K15 Premium, Methocel K100M Premium from Dows Chemicals), preferably between 2,308 and 9,030 mPa-s (e.g. Methocel K4M Premium and Methocel K15M Premium from Dows Chemical), more preferably between 2,663-4,970 mPa-s (e.g.
  • Methocel K4M Premium from Dows Chemicals chitosan, xanthan gum, guar gum, tragacanth, locust been gum, acacia gum, carbomers, glyceryl (di)behenate (e.g. Compritol® 888 ATO from Gattefosse), glyceryl palmitostearate (such as Precirol® from Gattefosse), ethylcellulose, polyvinyl acetate (Kollicoat® SR 30D) and polymethacrylates such as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1 (e.g.
  • the powder blend in step a) of the method of the present invention may optionally comprise at least one further additive.
  • additive refers to a non-therapeutic agent added to the formulation to provide a desired consistency, viscosity or stabilizing effect.
  • the at least one further additive is selected from pharmaceutically acceptable additives like glidants, plasticizers, lubricants, stabilizers, preservatives, antioxidants, humectants, protective colloids, dyes, permeation enhancers and protease inhibitors.
  • the inventive method in its most general form, comprises as first step, step a), providing a powder blend comprising the extrusion-spheronization aid, the disintegrant, and the at least one further excipient selected from the group consisting of fillers, sustained release agents and combinations thereof.
  • the individual components of the powder blend i.e. the extrusion- spheronization aid, the disintegrant, and the at least one further excipient, as defined above, can be provided as powders or granules.
  • the general properties of said powders or granules, such as grain size, grain size distribution or bulk density etc., suitable for use in the preparation of solid dosage forms by wet granulation, extrusion and spheronization are known by the person skilled the art.
  • the at least one antibody or functional fragment thereof, the buffer (buffer salt) and/or the surfactant are added directly to the powder blend.
  • the at least one antibody or functional fragment thereof may be added directly to the powder blend as a powder or as granules.
  • the at least one antibody or functional fragment thereof can be added as a powder comprising particles containing antibodies or functional fragments thereof, e.g. as a lyophilized, spray dried, air dried or vacuum dried powder.
  • the surfactant can be added as a powder or granules comprising the surfactant.
  • step a) can be mixed to give rise to the powder blend by a conventional mixing device.
  • mixing devices or blenders are known in the art and include for example a double-paddle mixer with blades counter-rotating at different speeds. If the grain sizes of the individual powdered components of step a) need to be further reduced before proceeding to step b), the powders can be grinded during the dry mixing step, with the help of appropriate mixing equipment.
  • the mixing device for the dry mixing is also used for the wet mixing (i.e. wet granulation or wetting) in step b).
  • the dry mixing stage is performed typically for about 10 minutes at 50 rpm of the blades.
  • step b) of the inventive method a binding liquid, is added to the powder blend from step a), preferably slowly and under continuous mixing, to obtain a wet mass.
  • This step is called wet granulating, wet mixing or wetting, and is carried out for a defined period of time, which may vary depending on the amount of material that is to be mixed.
  • the term "wet granulating” as used herein is understood to be equivalent in meaning to "wet mixing" or "wetting”.
  • the at least one antibody or functional fragment thereof, the buffer and/or the surfactant are comprised in the binding liquid.
  • the manner in which the at least one antibody or functional fragment thereof is introduced into the binding liquid is not particularly limited.
  • the at least one antibody or functional fragment thereof can be added to the binding liquid as a powder comprising particles containing antibodies or functional fragments thereof, e.g. as a lyophilized, spray dried, air dried or vacuum dried powder, and thereby directly reconstitute the antibody or functional fragment thereof in the binding liquid.
  • the at least one antibody or functional fragment thereof can be added already in solution, e.g. as part of a buffered aqueous solution.
  • the surfactant may be introduced into the binding liquid as a powder or as granules comprising the surfactant, or as a solution or suspension comprising the surfactant.
  • the total volume of binding liquid to be added to a defined amount powder blend from step a) is sufficient to produce a wet mass suitable for extrusion.
  • the total volume of binding liquid to be added to a defined amount powder blend from step a) is high enough to ensure that the wet mass obtained in step b) has sufficient cohesion and plasticity to permit extrusion of the wet mass, but low enough not to exceed the liquid uptake capacity of the powder blend.
  • the total volume of binding liquid to be added to produce a wet mass suitable for extrusion may vary depending on the final composition of the powder blend from step a), and can be determined by those skilled in the art.
  • the required total volume of binding liquid to be added can for example be experimentally determined by measurements of Torque or power consumption of the wet mass.
  • the powder blend in step a) or the binding liquid of step b) further comprises a binder.
  • Suitable binder to be used in accordance with the present invention are not particularly limited and include for example hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone.
  • step c) of the method of the present invention the wet mass from step b) is extruded, preferably at a controlled speed, while, preferably continuously, collecting an extrudate.
  • suitable extruders for the purpose of the inventive method are known in the art. Examples of suitable extruders include single screw extruder, twin-screw extruder, screen extruder, RAM extruder.
  • the extruder is a single-screw extruder (e.g. Caleva Multi-Lab). Suitable settings for the extruder can be determined by those skilled in the art.
  • the extruder includes a die plate with 1 mm diameter and 1 mm depth holes and a screw speed of 50 to 200 rpm, preferably about 150 rpm.
  • step d) of the method of the present invention the extrudate of step c) is fed to a spheronizer and spheronized to obtain individual wet spheroids.
  • the spheronizer and the spheronizer settings are not particularly limited. Examples of suitable spheronizers include the Caleva Multilab and larger scale spheronizers from Caleva and other companies.
  • the spheronizer consists of a grooved plate that by rotation breaks the extrudate from step c) into smaller fragments, which, depending on plate design, time, speed and formulation of the extrudate become round. Examples of suitable spheronization settings are for example 5 minutes at 1500 rpm.
  • step e) of the method of the present invention the wet spheroids from step d) are dried to obtain the final solid dosage form.
  • the solvent of the binding liquid is removed.
  • Means to dry wet spheroids after spheronization are known in the art, and include for example a fluidized bed, a drying cabinet or an oven. The drying may further be assisted by vacuum.
  • Activity and stability of antibodies and functional fragments thereof as used for the present invention are very sensitive to external stress like temperature fluctuations and particularly to elevated temperatures.
  • the temperature during drying is such as to protect the activity and stability of the antibodies and functional fragments thereof, and at the same time allow efficient drying of the wet spheroids to ensure long-term stability and activity of the at least one antibody or functional fragment thereof in the final solid dosage form prepared by the inventive method.
  • the drying of the wet spheroids is carried out at a temperature lower than 55°C, preferably lower than 50 °C, more preferably lower than 45 °C, even more preferably at about 40 °C.
  • the period of time over which the wet spheroids are dried is not particularly limited, and depends on the means used to dry the wet spheroids and the targeted residual moisture level of the solid dosage form.
  • the wet spheroids from step d) are dried in a fluidized bed, oven, or drying cabinet drying cabinet for 0.5 to 48 h, preferably 0.5 to 24 h, more preferably 2 to 18 h, even more preferably 4 to 16 h, even more preferably 8 to 14 h.
  • the wet spheroids may be dried until a sufficiently dry solid dosage form is obtained.
  • the solid dosage form is sufficiently dry, when a large proportion of the solvent used (preferably water) in the binding liquid has been removed by evaporation.
  • the solid dosage form is understood to be sufficiently dry, when the residual solvent (preferably water) content of the solid dosage form (i.e.
  • the residual moisture level of the solid dosage form is less than 20 wt.-%, preferably less than 15 wt.-%, more preferably less than 10 wt.-%, even more preferably less than 8 wt.-%, even more preferably less than 5 %, most preferably less than 3 wt.-%, 2 wt.-%, 1 wt.-% or 0.5 wt.-%, relative to the total weight of the solid dosage form.
  • the conditions during preparation of the solid dosage form are such as to be conducive to the activity and stability of the antibodies and functional fragments (e.g. by avoiding elevated temperatures, pressures, shear forces, enzymatic contaminations, etc.). Therefore, in one embodiment of the present invention at any time during steps a) to d) the temperature of the antibody or functional fragment thereof is lower than 55 °C, preferably lower than 50 °C, more preferably lower than 45 °C, even more preferably lower than 40 °C, even more preferably lower than 35 °C, most preferably lower than 30 °C.
  • the temperature of the at least one antibody or functional fragment thereof is lower than the melting temperature (Tm) of the at least one antibody or functional fragment thereof.
  • Tm melting temperature
  • the temperature is to be lower than the melting temperature (Tm) of the antibody or functional fragment thereof with the lowest Tm.
  • the temperature of the solid dosage form comprising the at least one antibody or functional fragment thereof at any time during step f) is lower than the melting temperature (Tm) of the at least one antibody or functional fragment thereof.
  • the solid dosage form prepared by the method of the present invention is an immediate release dosage form.
  • immediate release is meant to describe those solid dosage forms in which more than 50 %, preferably more than 60 %, even more preferably more than 70 %, etc., of the antibody or functional fragment thereof is released from the solid dosage form within about 2 h, preferably within about 1 h, even more preferably within about 0.5 h, of immersion in an aqueous solution.
  • aqueous solution as used herein may refer to solution or suspension of which a large part is water (e.g.
  • aqueous buffered solution refers to an aqueous solution comprising a buffer.
  • the solid dosage form may be an immediate release dosage form after completion of step e) of the inventive method.
  • additional coatings that modify the release of the at least one antibody or functional fragment thereof from the solid dosage form e.g. in the form of a sustained release coating or a delayed release coating, may be applied after completion of step e) in accordance with the present invention.
  • the solid dosage form can be immersed in a defined volume of aqueous solution for a defined period of the time and the resulting concentration of or functional fragment in the aqueous solution can be determine.
  • Means to determine an antibody concentration in an aqueous solution include for example by measuring the absorbance at 280nm or by using a colorimetric, reagent-based protein assay techniques like Bradford assay or by ELISA.
  • the solid dosage form is an immediate release dosage form after completion of step e), allowing the recovery of at least 80 %, preferably at least 85 %, more preferably at least 90 %, even more preferably at least 92 %, even more preferably at least 93 %, even more preferably at least 95 %, even more preferably at least 97 %, even more preferably at least 98 %, of the at least one antibody or functional fragment thereof from the solid dosage form within 1 h of continuously immersing the solid dosage form in an aqueous buffer solution under constant movement.
  • aqueous buffered solution aqueous buffered solution
  • the buffer volume used for dissolution testing can be adapted for instance using mini-vessels in the apparatus I or II to allow reduction of volume required and to be more biorelevant. Release of antibodies or functional fragments thereof during dissolution can be quantified offline by an ELISA method.
  • the at least one further excipient to be included in step a) of the inventive method is a substance that enables fast dissolution of the solid dosage form.
  • excipients for use in an immediate release solid dosage form prepared by the inventive method are fillers and may include one or more selected from dextrose, lactose, lactose monohydrate, lactose anhydrous, mannitol, sorbitol, xylitol, sucrose, glucose, raffinose, trehalose, dicalcium phosphate, oxides of magnesium or silicon, titanium carbonate, calcium carbonate, magnesium phosphate, porous calcium phosphate or porous magnesium phosphate, amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid, and asparagine and respective salts thereof, propylene glycol, polyethylene glycol; preferably dextrose, mannitol, sucrose, sorbitol, xylitol, trehalose and dicalcium phosphate, and amino acids such as arginine, hist
  • the powder blend in step a) comprises microcrystalline cellulose as extrusion-spheronization aid; sodium starch glycolate, as disintegrant; and sorbitol or mannitol, preferably sorbitol, as filler.
  • the powder blend in step a) comprises 20 to 90 %, preferably 30 to 80 %, more preferably 40 to 75%, even more preferably 45 to 70 %, most preferably about 45 to 50 % extrusion-spheronization aid; 0.5 to 50 %, preferably 0.5 to 40, more preferably 1 to 35%, even more preferably 1 to 30%, even more preferably 1 to 15%, most preferably about 1 to 10 %, alternatively most preferably 10 to 30 %, of the disintegrant; and 2.5 to 55 %, preferably 5 to 50 %, more preferably 10 to 40 %, even more preferably 20 to 40 %, most preferably about 30 to 40 %, alternatively most preferably 20 to 30 %, of a filler (preferably sorbitol, sucrose, trehalose, or mannitol, amino acids such as arginine, histidine, g
  • a filler preferably sorbitol, sucrose, trehalose, or mannitol, amino
  • the powder blend in step a) comprises 20 to 70 %, preferably 30 to 60 %, more preferably 40 to 50%, even more preferably about 45 %, extrusion-spheronization aid; 0.5 to 30 %, preferably 0.5 to 20 %, more preferably 1 to 15%, even more preferably 1 to 10 %, of the disintegrant; 5 to 50 %, preferably 10 to 45 %, more preferably 20 to 40 %, even more preferably 30 to 40 %, of a filler (preferably sucrose, trehalose, sorbitol or mannitol amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof,
  • a filler preferably sucrose, trehalose, sorbitol or mannitol amino acids such as arginine, histidine, glycine, a
  • sustained release is used to describe those solid dosage forms, which release a substantial fraction of antibody or functional fragment thereof from the solid dosage form over a prolonged period of time, e.g. over at least 6 h, preferably at least 8h, at least 10 h, at least 12 h, at least 14 h, at least 16 h, at least 18 h, or at least 24 h, etc.
  • the solid dosage form is a sustained release dosage form, allowing the recovery of at least 45%, preferably at least 55%, more preferably at least 65 %, even more preferably at least 75 %, even more preferably at least 80 %, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 93%, even more preferably at least 95 %, even more preferably at least 98 % of the at least one antibody or functional fragment thereof from the solid dosage form within a defined time period (e.g.
  • the solid dosage form is a sustained release dosage form, allowing a sustained release of the at least one antibody or functional fragment thereof over a time period of at least 5 h, preferably at least 10 h, more preferably at least 12 h, even more preferably at least 20 h, most preferably at least 24 h, upon continuously immersing the solid dosage form in an aqueous solution.
  • the solid dosage form is a sustained release dosage form, allowing a sustained release of the at least one antibody or functional fragment thereof over a time period of at least 8 h, at least 10 h, at least 12 h, at least 14 h, or at least 16 h upon continuously immersing the solid dosage form in an aqueous buffer solution under constant movement.
  • sustained release solid dosage form of an active biological agent in the form of an antibody or functional fragment thereof, exhibiting limited systemic absorption can be desirable.
  • at least one further excipient is a sustained release agent, which may be selected from sustained release polymers.
  • sustained release polymers include nonionic poly(ethylene oxide) polymers with a molecular weight between 100,000 and 7,000,000, preferably a molecular weight of about 100,000 (e.g.
  • Polyox® N- 10NF from Dow Chemicals HPMC 2208 type with a viscosity at 2 wt.-% in water at 20°C between 3 and 100000 mPa-s (such as Methocel K3 Premium LV, Methocel K100 Premium LV, Methocel K4M Premium, Methocel K15 Premium, Methocel K100M Premium from Dow Chemicals), preferably between 2,308 and 9,030 mPa-s (e.g. Methocel K4M Premium and Methocel K15M Premium from Dows Chemical), more preferably between 2,663-4,970 mPa-s (e.g.
  • Methocel K4M Premium from Dow Chemicals chitosan, xanthan gum, guar gum, tragacanth, locust been gum, acacia gum, carbomers, glyceryl (di)behenate (e.g. Compritol® 888 ATO from Gattefosse); glyceryl palmitostearate (such as Precirol®); polymethacrylates such as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1 (e.g.
  • Eudragit® NE 30D, Eudragit® NE 40D and Eudragit® NM 30D ethylcellulose; preferably nonionic poly(ethylene oxide) polymers with a molecular weight of about 100,000 (Polyox® N-10NF); HPMC 2208 type with a viscosity at 2% in water at 20°C of 2,663-4,970 mPa-s (Methocel K4M, Dow Chemicals); and glyceryl (di)behenate (Compritol® 888 ATO).
  • the powder blend in step a) comprises microcrystalline cellulose as extrusion-spheronization aid; sodium starch glycolate, as disintegrant; and Polyox® N-10NF or Methocel K4M as the at least one further excipient.
  • the powder blend in step a) comprises 20 to 90 %, preferably 45 to 80 %, more preferably 50 to 80 %, even more preferably 60 to 75 %, most preferably about 70 to 75 % extrusion- spheronization aid; 0.1 to 45 %, preferably 0.5 to 35%, more preferably 1 to 30 %, even more preferably 1 to 25 %, even more preferably 1 or 15 %, most preferably about 5 to 15 % of the disintegrant; and 0.5 to 30 %, preferably 1 to 20 %, more preferably 2.5 to 12.5 %, even more preferably 2.5 to 10 %, most preferably about 2.5 to 7.5 %, of the at least one further excipient comprising at least one sustained release agent.
  • step a) at least two further excipients are added in step a), wherein the first further excipient is a sustained release agent, preferably a sustained release polymer, and the second further excipient is a filler, preferably sucrose, trehalose, sorbitol or mannitol, amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof, and combinations thereof, more preferably sorbitol.
  • the first further excipient is a sustained release agent, preferably a sustained release polymer
  • the second further excipient is a filler, preferably sucrose, trehalose, sorbitol or mannitol, amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspart
  • the powder blend in step a) may comprise 20 to 90 %, preferably 45 to 85 %, more preferably 50 to 80 %, even more preferably 60 to 80 %, most preferably about 75 % extrusion-spheronization aid; 0.1 to 40 %, preferably 0.5 to 30%, more preferably 1 to 20%, even more preferably 1 to 15 %, most preferably 1 to 10 % of the disintegrant; 1 to 30 %, preferably 1 to 20 %, more preferably 2.5 to 12.5 %, even more preferably 2.5 to 10 %, most preferably about 2.5 to 7.5 %, of the sustained release agent; and 0.5 to 30 %, preferably 1 to 20 %, more preferably 1 to 15 %, even more preferably 5 to 15 %, most preferably about 10 % of the filler.
  • the powder blend in step a) comprises microcrystalline cellulose as extrusion-spheronization aid; glyceryl (di)behenate as first further excipient; and a filler, preferably sorbitol, sucrose, trehalose, or mannitol, or amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof, and combinations thereof, as second further excipient.
  • a filler preferably sorbitol, sucrose, trehalose, or mannitol, or amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof, and combinations thereof, as second further excipient.
  • the powder blend in step a) comprises 30 to 85 %, preferably 45 to 80%, more preferably 50 to 80 %, even more preferably about 75 % extrusion- spheronization aid; 1 to 35 %, preferably 1 to 25 %, more preferably 2.5 to 15 %, even more preferably about 2.5 to 10 %, of glyceryl (di)behenate as the first further excipient; 2.5 to 45 %, preferably 5 to 40%, more preferably 10 to 35%, even more preferably 10 to 25% , of the second further excipient in the form of a filler, preferably sucrose, trehalose, sorbitol or mannitol, more preferably sorbitol.
  • a filler preferably sucrose, trehalose, sorbitol or mannitol, more preferably sorbitol.
  • the binding liquid of step b) of the method of the present invention is not particularly limited, as long as it ensures the stability and activity of the antibody or functional fragment thereof and allows its use as a wetting solution for the powder blend of step a) that is at least in part absorbed by the powder blend.
  • the binding liquid can be any solvent or mixture of solvents that fulfill these criteria.
  • the binding liquid is an aqueous solution.
  • the binding liquid comprises at least one buffer to further ensure the stability of the antibody or functional fragment thereof. Suitable buffers for use in combination with antibodies or functional fragments thereof are known in the art and include acetate, citrate, histidine, TRIS, and phosphate buffers.
  • the binding liquid may furthermore comprise a stabilizer.
  • a stabilizer for use in combination with antibodies or functional fragments thereof are known in the art and include polyols (sorbitol, mannitol, glycerol, propyleneglycol, polyethyleneglycol), sugars (sucrose, trehalose, glucose, raffinose), cyclodextrins, and amino acids such as arginine, histidine, glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and respective salts thereof.
  • the concentration of the at least one antibody or functional fragment thereof in the binding liquid or in the powder blend is not particularly limited.
  • the concentration of the at least one antibody or functional fragment thereof in the binding liquid or in the powder blend is such as to result in an amount of antibody or functional fragment thereof in the solid dosage form prepared by the method of the present invention that allows the administration of a therapeutically effective dose of the at least one antibody or functional fragment thereof as a single unit dose, for example in the form of a tablet, capsule, drinking straw (Xstraw®), or sachet stickpack comprising multiple solid dosage forms (e.g. in the form of multiple pellets, beads or granules).
  • administration relates to the manner and form in which the composition comes into first contact with the body of a patient.
  • the solid dosage form prepared by the inventive method can be administered orally, rectally or in any other way that results in the accumulation of the solid dosage form at the intended site of local application and/or absorption into body tissue.
  • the solid dosage form of the present invention is intended for oral administration.
  • a "therapeutically effective dose” is the amount of the at least one antibody or functional fragment thereof required to provide the desired therapeutic effect. The exact amount may vary for different antibodies or functional fragments thereof and/or for individual patients, but can be determined by one skilled in the art.
  • the concentration of the antibody in the binding liquid or in the powder blend is such to result in an amount of antibody or functional fragment thereof in the solid dosage form between 0.01 and 60 %, preferably 0.05 to 45 %, more preferably 0.1 to 30 %, even more preferably 0.5 to 25 %, even more preferably 1 to 20 %, even more preferably 1 to 15 %, even more preferably 2 to 15 %, most preferably 5 to 15 %, relative to the total weight of the solid dosage form after step e).
  • the at least one antibody or functional fragment thereof is comprised in the binding liquid in a concentration (w/v) of 0.01 to 1000 mg/ml, preferably 0.1 to 500 mg/ml, more preferably 1 to 200 mg/ml, even more preferably 5 to 100 mg/ml, even more preferably 10 to 50 mg/ml.
  • concentration w/v
  • the amount or concentration of antibody or functional fragment thereof in the binding liquid needs to be adjusted depending on the total volume of binding liquid to be added to a defined amount and composition of powder blend from step a), in order to realize a desired loading of antibody or functional fragment thereof relative to the total weight of the final solid dosage form.
  • the at least one antibody or functional fragment thereof is comprised in the powder blend in a concentration (w/w) of 0.01 to 60 %, preferably 0.05 to 45 %, more preferably 0.1 to 30 %, even more preferably 0.5 to 25 %, even more preferably 1 to 20 %, even more preferably 1 to 15 %.
  • the amount of the antibody or functional fragment thereof in the solid dosage form prepared by the inventive method will vary according to the pharmacological activity of the antibody or functional fragment, the indication to be treated, the targeted dosing regimen, the projected method of administration, the integrity, stability and dissolution behavior of the final composition and other similar reasons.
  • the amount of the at least one antibody or functional fragment thereof is at least 0.01 %, preferably at least 0.05 %, more preferably at least 0.1 %, even more preferably at least 1 %, most preferably at least 2 %, relative to the total weight of the solid dosage form, preferably after step e) of the inventive method.
  • the he amount of the antibody or functional fragment thereof is generally up to 60 %, preferably up to 45 %, more preferably at least 35 %, even more preferably up to 30 %, even more preferably up to 25 %, even more preferably up to 20 %, relative to the total weight of the solid dosage form, preferably after step e) of the inventive method.
  • the solid dosage form, prepared according to steps a) to e) of the inventive as described above is an immediate release dosage form, as step f) at least one additional coating in the form of a sustained release coating may be applied after step e).
  • the sustained release coating is applied by spray coating, for example using fluidized-bed spray coating.
  • the sustained release coating may for example be applied as a coating liquid, e.g. in the form of an aqueous suspension (dispersion) or organic solution comprising sustained release coating materials and optional further excipients, such as plasticizers, anti-tacking excipients and coalescence enhancers.
  • Sustained release coating materials for the sustained release coating of a solid dosage form in step f) are known in the art.
  • Suitable coating materials for use in a sustained release coating are sustained release polymers, such as polymethacrylates such as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1 (e.g. Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30D and Eudragit® RS 12.5), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2 (e.g.
  • Sustained release polymers for use in the sustained release coating may be provided as solids, e.g. in the form of a powder or granules, or as suspensions (dispersion), e.g. an aqueous suspension.
  • the sustained release polymer is provided as a suspension.
  • excipients for use in the sustained release coating comprise plasticizers, anti-tacking agents, coalescence enhancer, glidants, antioxidants, humectants, protective colloids, dyes and fillers.
  • the inventive method allows the activity and stability of the at least one antibody or functional fragment thereof to be preserved in the solid dosage form prepared according to the inventive method.
  • the stability and activity of an antibody or fragment thereof can be estimated for example by determining the fraction of an antibody or functional fragment thereof present as dimers and other aggregates.
  • the fraction of total content of antibody or functional fragment thereof present in the solid dosage form as dimers and other aggregates does not exceed by more than 15%, preferably 10 %, more preferably 8 %, even more preferably 7%, even more preferably 5 %, 3 %, 2 %, or 1 .5 %, the fraction of total antibody or functional fragment thereof present as dimers and other aggregates at the time of adding the antibody or functional fragment thereof to the binding liquid.
  • fraction of a polypeptide present as dimers and other aggregates are known in the art, and include for example Size Exclusion Chromatography (SEC).
  • SEC Size Exclusion Chromatography
  • the stability and activity of an antibody or functional fragment thereof can also be estimated for example by determining the fraction of an antibody or functional fragment thereof present as fragments of the full-length antibody or functional fragment thereof. Therefore, in another embodiment of the present invention, the fraction of total content of antibody or functional fragment thereof present in the solid dosage form as fragments of the full-length antibody or functional fragment thereof does not increase substantially compared to the time of adding the antibody or functional fragment thereof to the binding liquid.
  • the fraction of total content of antibody or functional fragment thereof present in the solid dosage form as fragments of the full-length antibody or fragment thereof does not exceed by more than 15%, preferably 10 %, more preferably 8 %, even more preferably 7%, even more preferably 5 %, 3 %, 2 %, 1 .5 %, or 1 %, the fraction of total content of antibody or functional fragment thereof present as fragments of the full-length antibody or functional fragment thereof at the time of adding the antibody or functional fragment thereof to the binding liquid.
  • Methods to determine the fraction of an antibody or functional fragment thereof present as fragments of the full-length antibody or functional fragment thereof are known in the art, and include for example microchip electrophoresis analysis.
  • the antibody or functional fragment thereof is suitable for use in the topical treatment in the gastrointestinal tract of a patient.
  • topical treatment in the context of the present invention, is used to describe the local application of the solid dosage form, as opposed to the systemic application of a dosage form comprising antibodies or functional fragments thereof, e.g. by infusion, injection or implantation.
  • gastrointestinal tract as used herein describes the system of organs of the human body, that includes all structures between mouth and anus, forming a continuous passage, and is responsible for digesting ingested material, absorbing nutrients and expelling faeces.
  • patient refers to a living organism suffering from or prone to a condition that can be treated or prevented by the administration of the at least one antibody or functional fragment thereof. In a preferred embodiment, the patient is a human.
  • a solid dosage form enables once-daily, several times a day, once-in-two days, etc. delivery of the above classes of antibodies and functional fragments thereof.
  • the topical treatment in the gastrointestinal tract e.g. the ileum or the large intestine, allows for specific targeting of the gastrointestinal wall, for enhanced treatment of diseases of the ileum and large intestine, by providing high local concentration of antibody or functional fragment thereof, while minimizing side effects that occur because of release of drugs in the upper gastrointestinal tract or unnecessary systemic absorption. Therefore in another embodiment of the present invention the solid dosage form prepared by the inventive method is for use in the treatment of a disease in the gastrointestinal tract, preferably in the ileum and the large intestine.
  • diseases include e.g.
  • the solid dosage form prepared by the inventive method is for use in the treatment of IBD, e.g. Crohn's disease or ulcerative colitis.
  • the solid dosage form prepared by the method of the present invention is for oral or rectal, preferably oral, administration.
  • Oral administration in context of the present invention means the introduction of the solid dosage form into gastrointestinal tract via the mouth.
  • Rectal administration in context of the present invention means the introduction of the solid dosage form into gastrointestinal tract via the anus.
  • At least one additional coating in the form of a delayed release coating is applied to the solid dosage form after drying in step e), or after step f) if at least one additional coating in the form of a sustained release coating is applied as step f).
  • a delayed release coating within the meaning of the present invention is a coating that prevents the release of the at least one antibody or functional fragment thereof from the solid dosage form, until a specific event, e.g. in the form of a chemical or enzymatic trigger or the lapse of a defined amount of time immersed in solution, occurs.
  • the solid dosage form prepared by the method of the present invention is for oral administration, in the form of a pellet, bead, mini sphere, mini tablet, or granule coated with a delayed release coating that prevents the release of the composition for example before the jejunum or before the ileum of the small intestine, preferably before the terminal ileum, more preferably before the ileocolonic region, alternatively before the ascending colon, before the transverse colon or before the descending colon, of the gastrointestinal tract.
  • the ileocolonic region is the region of the gastrointestinal tract where the small intestine merges with the large intestine.
  • the large intestine is the penultimate section of the gastrointestinal tract and can be further subdivided into cecum, colon and rectum.
  • the colon is further subdivided into ascending, transverse and descending colon.
  • the terminal ileum is the penultimate section of the small intestine and is directly adjacent to the cecum.
  • the manner in which the delayed release coating is applied is not particularly limited, as long as it does not affect the stability and activity of the at least one antibody or functional fragment thereof in the solid dosage form.
  • Methods for applying delayed release coatings are known in the art.
  • the delayed release coating is applied by spray coating, preferably fluidized-bed spray coating.
  • Coating materials for the delayed release of a solid dosage form, in particular for targeted release in the jejunum, the ileum or the large intestine, upon oral administration are known in the art. They can be subdivided into coating materials that disintegrate above a specific pH, coating materials that disintegrate after a specific residence time in the gastrointestinal tract and coating materials that disintegrate due enzymatic triggers specific to the microflora of a specific region of the intestines. Coating materials of these three different categories for targeting to the large intestine have been reviewed for example in Bansal et al. (Polim. Med. 2014, 44, 2,109-1 18).
  • the delayed release coating comprises at least one component selected from coating materials that disintegrate pH-dependently, coating materials that disintegrate time-dependently, coating materials that disintegrate due to enzymatic triggers in the large intestinal environment, and combinations thereof.
  • Preferred coating materials among coating materials that disintegrate pH-dependently are selected from poly vinyl acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate HP-50, HP-55 or HP-55S, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(methacrylic acid, ethyl acrylate) 1 :1 (Eudragit® L100-55, Eudragit® L30D-55), poly(methacrylic acid, methyl methacrylate) 1 :1 (Eudragit® L-100, Eudragit® L12.5), poly(methacrylic acid, methyl methacrylate) 1 :2 (Eudragit® S-100, Eudragit® S12,5, Eudragit® FS30D), and combinations thereof.
  • Preferred coating materials that disintegrate time-dependently are selected from polymethacrylates such as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2 (e.g. Eudragit® RL 30D, Eudragit® RL100, Eudragit® RL PO, and Eudragit® RL 12.5), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1 (e.g.
  • Eudragit® RS 30D Eudragit® RS 100, Eudragit® RS PO, and Eudragit® RS 12.5), or poly(ethylacrylate, methylmethacrylate) 2:1 (e.g. Eudragit® NE 30D, Eudragit® NE 40D, Eudragit® NM 30D), polyvinyl acetate (Kollicoat® SR 30D), ethylcellulose, and combinations thereof.
  • Preferred coating materials among coating materials that disintegrate due to enzymatic triggers in the intestinal environment are selected from chondroitin sulfate, pectin, guar gum, chitosan, inulin, lactulose, raffinose, stachyose, alginate, dextran, xanthan gum, locust bean gum, arabinogalactan, amylose, amylopectin, pullulan, carrageenan, cyclodextrin, scleroglucan, chitin, curdulan, levan, starch, resistant starch, azo compounds being degraded by azo bonds splitting bacteria, and combinations thereof.
  • the coating material for the delayed release coating comprises one, two, three, etc., component(s) selected from the coating materials that disintegrate pH-dependently, the coating materials that disintegrate time-dependently, and the coating materials that disintegrate due to enzymatic triggers in the intestinal environment, listed above, and combinations thereof.
  • the delayed release coating comprises a combination of at least one coating material that disintegrates pH-dependently and at least one coating material that disintegrates due to enzymatic triggers in the intestinal environment.
  • a delayed release coating can be designed to focus the delivery of the antibody or functional fragment thereof entirely in the large intestine, beginning at the cecum, and continuing through the ascending, transverse, and descending colon, and ending in the sigmoid colon.
  • a delayed release coating can be designed to begin the delivery of the antibody or functional fragment thereof in the jejunum and end the release in the transverse colon.
  • the delayed release coating comprises a combination of at least one pH sensitive (enteric) polymer, e.g.
  • the delayed release coating is a combination of poly(methacrylic acid, methyl methacrylate) 1 :2 and resistant starch (e.g. Phloral® technology).
  • the delayed release coating comprising at least one enteric polymer, e.g.
  • at least one polysaccharide, e.g. resistant starch may be dispersed in an organic solvent, a mixture of organic solvents or a mixture of at least one organic solvent and water, and then applied to the solid dosage form e.g. by fluidized-bed spray coating.
  • the delayed release coating comprises i) an inner coating comprising partially neutralized enteric polymers adjusted to pH 8 (preferably poly(methacrylic acid, methyl methacrylate) 1 :2 adjusted to pH 8) and containing a buffer salt, and ii) an outer coating comprising a combination of at least one enteric polymer (preferably poly (methacrylic acid, methyl methacrylate) 1 :2) and at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch, and combinations thereof, preferably resistant starch.
  • enteric polymer preferably poly (methacrylic acid, methyl methacrylate) 1 :2 adjusted to pH 8
  • an outer coating comprising a combination of at least one enteric polymer (preferably poly
  • delayed release coatings can be found among the embodiments disclosed in WO2007122374A2.
  • the above described delayed release coatings optionally comprise at least one excipients listed in one of the embodiments above (e.g. surfactants, fillers, or further additives).
  • a sachet/stickpack, capsule e.g. a hard or soft gelatin capsule
  • HPMC capsule e.g. Xstraw® from Harro Hofliger
  • tablet multiparticulate drug delivery system
  • the multiparticulate drug delivery system may comprise a total amount of the at least one antibody or functional fragment thereof suitable for oral administration to a human patient.
  • the sachet/stickpacks, capsule, drinking straws or tablets comprises a therapeutically effective dose of the at least one antibody or functional fragment thereof suitable for oral administration to a human patient.
  • multiple solid dosage forms prepared by steps a) to d) or steps a) to f) of the inventive method, as described in one of the inventive embodiments above, may be combined into a multiparticulate drug delivery system, e.g. a tablet or capsule. How to prepare such tablets or capsules comprising multiple units is known in the art. The thus prepared tablet or capsule may then be coated with a delayed release coating as described above.
  • the present invention further relates to solid dosage forms prepared by the method of the present invention as defined by any one of the embodiments described above.
  • the inventive solid dosage forms may be in the form of pellets, beads, mini spheres, granules or mini tablets.
  • the present invention also relates to a multiparticulate drug delivery system in the form of a sachet/stickpack, capsule, drinking straw (Xstraw®), or tablet comprising multiple unit solid dosage forms prepared by the inventive method described above.
  • the present invention relates to said solid dosage forms/multiparticulate drug delivery systems for use in the treatment of a gastrointestinal disease, preferably IBD, colorectal cancer, small intestine cancer, celiac disease or gastrointestinal infections (e.g. Clostridium difficile infection), more preferably IBD, e.g. Crohn's disease or ulcerative colitis, more preferably Crohn's disease or ulcerative colitis.
  • a gastrointestinal disease preferably IBD, colorectal cancer, small intestine cancer, celiac disease or gastrointestinal infections (e.g. Clostridium difficile infection), more preferably IBD, e.g. Crohn's disease or ulcerative colitis, more preferably Crohn's disease or ulcerative colitis.
  • the present invention also relates to solid dosage forms/multiparticulate drug delivery systems prepared by the inventive method described above for use in the topical treatment in the gastrointestinal tract of a patient.
  • the present invention relates said inventive solid dosage forms/multiparticulate drug delivery systems for use in the treatment of a patient suffering from a gastrointestinal disease, preferably IBD, colorectal cancer, small intestine cancer, celiac disease or gastrointestinal infections, more preferably IBD.
  • a gastrointestinal disease preferably IBD, colorectal cancer, small intestine cancer, celiac disease or gastrointestinal infections, more preferably IBD.
  • the present invention relates to a multiparticulate drug delivery system comprising a plurality of solid dosage form units (i.e. single solid dosage forms), each solid dosage form unit comprising at least one antibody or functional fragment thereof, a surfactant, an extrusion-spheronization aid, a buffer (buffer salt), a disintegrant and at least one further excipient selected from the group consisting of fillers, sustained release agents and combinations thereof, and optional further additives, and preferably each solid dosage form unit having a predetermined axis and the same predetermined cross-sectional profile, wherein at least 80% by number of those solid dosage form units, preferably 90%, more preferably 95%, have a median aspect ratio between 0.7 and 1.7, the aspect ratio being defined as solid dosage form unit length along the predetermined axis divided by the smallest cross-sectional dimension.
  • solid dosage form units i.e. single solid dosage forms
  • each solid dosage form unit comprising at least one antibody or functional fragment thereof, a surfactant, an extrusion-sp
  • the median aspect ratio is above 0.8, preferably above 0.9, and below 1 .6, preferably below 1.5, more preferably 1 .4, even more preferably below 1 .3, even more preferably below 1 .2, most preferably about 1 .
  • the solid dosage form units have a span of aspect ratio less than 0.9, preferably less than 0.8, more preferably less than 0.7, even more preferably less than 0.6, most preferably less than 0.5.
  • aspect ratio, predetermined axis, predetermined cross-sectional profile and span it is referred to disclosure of EP 2 512 453. It is to be understood that the above definitions and embodiments regarding aspect ratio and span of the solid dosage form units equally apply to the inventive solid dosage forms according to any one of the embodiments above and to the solid dosage forms prepared by any one of the embodiments of the inventive method described above.
  • the multiparticulate drug delivery system of the present invention allows the recovery of at least 80 %, preferably at least 85%, more preferably at least 93 %, even more preferably at least 95 %, even more preferably at least 97%, even more preferably at least 98%, of the at least one antibody or functional fragment thereof from the solid dosage form units.
  • the multiparticulate drug delivery system of the present invention allows the recovery of at least 80 %, preferably at least 85%, more preferably at least 93 %, even more preferably at least 95 %, even more preferably at least 97%, even more preferably at least 98%, of the at least one antibody or functional fragment thereof from the solid dosage form units within 30 min, or 1 h, or 2 h, of continuously immersing the solid dosage form in an aqueous buffer solution under constant movement (immediate release).
  • the multiparticulate drug delivery system of the present invention allows the recovery of at least 80 %, preferably at least 85%, more preferably at least 93 %, even more preferably at least 95 %, even more preferably at least 97%, even more preferably at least 98%, of the at least one antibody or functional fragment thereof from the solid dosage form units within 4 h, or 6 h, or 8 h, or 10 h, or 12 h, or 14 h, or 16 h, or 18 h, or 20 h, or 22 h, or 24 h, or 26 h, or 28 h, or 30 h, or 32 h, or 34 h, or 36 h, etc., of continuously immersing the solid dosage form in an aqueous buffer solution under constant movement (sustained release).
  • the solid dosage form units comprised in the multiparticulate drug delivery system are prepared by extrusion-spheronization.
  • the solid dosage form units comprised in the multiparticulate drug delivery system are solid dosage forms prepared by extrusion- spheronization according to the method of any of the embodiments described above.
  • the solid dosage form units comprised in the multiparticulate drug delivery system are prepared by extrusion, and are non-spheronized solid dosage form units.
  • the multiparticulate drug delivery system is prepared from multiple solid dosage form units by compression, encapsulation or extrusion- spheronization and/or has the properties as defined in any of the embodiments described above relating to multiparticulate drug delivery systems and the method for the preparation thereof.
  • the multiparticulate drug delivery system or the individual solid dosage form units comprise a delayed release coating, which is applied as a further coating.
  • a delayed release coating which is applied as a further coating.
  • Further embodiments for the multiparticulate drug delivery system may be found in EP 2 512 453 and are applicable to the present invention independent of whether these embodiments are disclosed in EP 2 512 453 as referring to spheronized or non- spheronized solid dosage forms.
  • Citrate-TRIS buffer pH 7 preparation A solution of sodium citrate 100 mM (2.942 g and completed to 100.0 mL with purified water) was prepared. A solution of citric acid 100 mM (3.842 g dissolved and diluted to 200.0 ml with purified water) was prepared. The pH of the citric acid solution was adjusted to 3.5 with the sodium citrate solution. A TRIS solution 1 M (12.1 14 g and completed to 100.0 ml with purified water) was prepared. The pH of the citrate buffer was adjusted to pH 7.0 with the TRIS solution. Preparation of pellets
  • Dry mixing The excipients required for each batch (batch size: 10 g) were mixed using the Mixer attachment (double-paddle mixer) from the Caleva Multilab equipment for about 5 minutes predetermined period of time at 50 rpm.
  • the binding liquid (either deionized water, citrate-TRIS buffer pH 7 or adalimumab solution, including or not a predetermined surfactant concentration) was slowly added to the powder blend of excipients under mixing and mixed for a predetermined period of time and speed.
  • Extrusion The wet mass was then emptied from the mixer and extruded through 1 mm diameter and 1 mm depth holes of the extrusion die using a screw extruder at a constant speed (150 rpm) until all wet mass is extruded.
  • the wet extrudate was then fed to the spheronizer attachment, consisting of a grooved plate, which by rotation breaks the wet extrudates into smaller fragments that depending on time, speed and the nature of the individual components of the extrudate become then round (wet spheroids).
  • the extrudate was spheronized for a predetermined amount of time at a given speed.
  • Example 1 50/10 1500/6
  • Example 19 50/10 1500/10 Drying The wet pellets obtained from the spheronization step were then collected in a disposable weighing boat and dried overnight at 40°C in a drying cabinet.
  • a quantity of adalimumab loaded pellets was placed in a 5 ml cryo tube and 4.0 ml of buffer was added to yield a theoretical 1 mg/ml adalimumab concentration, based on the theoretical calculated adalimumab loading.
  • Citrate-TRIS buffer pH 7 was used unless stated otherwise. Samples are agitated during the entire duration of the experiment. Supernatant samples (200 ⁇ ) were taken at predetermined time points, centrifuged and the supernatant was analyzed in terms of total protein content, presence of aggregates (SEC) and fragmentation (electrophoresis) whenever specified.
  • Total protein content quantification (Bradford): Total protein quantification was done by colorimetry following the Bradford method with a Coomassie Plus assay (Thermo Fisher Scientific). Briefly, 6.6 ⁇ of sample were pipetted into to bottom of a 96-well plate and 200 ⁇ of Coomassie Plus reagent were added and mixed by agitation for 30 s at 500 rpm. The samples were then incubated at room temperature for 10 min after which the absorbance at 595 nm was recorded (Tecan plate reader) and the blank subtracted. Quantification was done using a freshly prepared standard curve.
  • Microchip Electrophoresis analysis (fragments): The supernatant (2 ⁇ ) of samples containing adalimumab were tested for the presence of fragments by microchip gel electrophoresis under non-reducing conditions. In all experiments a positive control of adalimumab 1 mg/ml in citrate-TRIS buffer pH 7 was used.
  • Size exclusion chromatography The supernatant of samples containing adalimumab was tested for the presence of aggregates (dimers, oligomers) by size exclusion chromatography (SEC). In all experiments a positive control of adalimumab 1 mg/ml in citrate-TRIS buffer pH 7 was used.
  • Adalimumab release from pellets containing the same excipient composition in the powder blending stage but granulated with different binding liquid compositions was assessed in citrate-TRIS buffer pH 7.
  • Pellet compositions as listed in Table 1 were prepared as described above and tested. Using 0.01 % Tween 20 as surfactant in the binding liquid during wet mixing/granulation significantly improved adalimumab recovery (Comparative Example 3) in comparison to the control formulation containing no surfactant (Comparative Example 2), however, it was not enough to prevent adsorption over time during dissolution.
  • Example 2 Using 0.05% (Example 1 ) or 0.1 % Tween® 20 (Example 4) further increased recovery adalimumab, allowing a complete recovery when 0.1 % Tween® 20 was used in the binding liquid containing adalimumab during the wet mixing ( Figure 2).
  • Compritol® 888 ATO was tested as a sustained release polymer, otherwise using the components and preparation as described above for the other sustained release dosage forms (0.1 % Tween® 20). The following pellet compositions were prepared and tested.
  • Table 5 immediate release solid dosage forms prepared with spray-dried adalimumab added during dry mixing
  • Pellets were also prepared starting with spray-dried adalimumab in the dry blending stage.
  • the binding liquid is an aqueous solution of Tween® 20 at different concentrations, ranging from 0.1 % to 0.5% w/v.
  • Tween® 20 concentration in the binding liquid resulted in fast dissolution with about 90% adalimumab recovered from the pellets, in comparison to pellets manufactured with only 0.1 % Tween® 20 (Comparative Example 4), where adalimumab could not be recovered even over a longer time period due to adsorption ( Figure 7).
  • Adalimumab release in citrate-TRIS buffer pH 7 from the matrix pellets could be effectively controlled by the Eudragit® RS 30D coating quantity applied on the adalimumab layered pellets ( Figure 8A). Additionally, no significant increase in adalimumab aggregates or fragments was observed in Example 19 pellet samples collected after 24 h in citrate-TRIS buffer pH 7, as determined by size exclusion chromatography and microchip electrophoresis, respectively ( Figure 8B), indicating that both the formulation and the manufacture steps, including the extrusion-spheronization process followed by a coating with sustained release polymer do not have a detrimental impact on the antibody.

Abstract

La présente invention concerne un procédé de préparation de formes galéniques solides à libération immédiate et prolongée, comprenant des anticorps et des fragments fonctionnels de ceux-ci, par granulation humide, extrusion et sphéronisation, éventuellement enrobées d'un enrobage à libération retardée, les formes galéniques solides préparées par le procédé et l'utilisation des formes galéniques solides en traitement topique dans le tractus gastro-intestinal d'un patient.
PCT/EP2018/074521 2017-09-20 2018-09-11 Procédé de préparation d'une forme galénique solide comprenant des anticorps par granulation humide, extrusion et sphéronisation WO2019057563A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
KR1020207008146A KR20200054984A (ko) 2017-09-20 2018-09-11 습식 과립화, 압출 및 구형화에 의한, 항체를 포함하는 고체 투여 형태의 제조 방법
MX2020003031A MX2020003031A (es) 2017-09-20 2018-09-11 Metodo para preparar una forma de dosificacion solida que comprende anticuerpos por granulacion humeda, extrusion y esferonizacion.
CA3075875A CA3075875A1 (fr) 2017-09-20 2018-09-11 Procede de preparation d'une forme galenique solide comprenant des anticorps par granulation humide, extrusion et spheronisation
JP2020515727A JP7316268B2 (ja) 2017-09-20 2018-09-11 湿式造粒、押出および球形化による抗体を含む固形剤形の調製方法
US16/646,336 US20200268675A1 (en) 2017-09-20 2018-09-11 Method for preparing a solid dosage form comprising antibodies by wet granulation, extrusion and spheronization
CN201880061124.7A CN111107841B (zh) 2017-09-20 2018-09-11 通过湿法制粒、挤出和滚圆制备包含抗体的固体剂型的方法
CN202310130247.4A CN116211832A (zh) 2017-09-20 2018-09-11 通过湿法制粒、挤出和滚圆制备包含抗体的固体剂型的方法
EP18768882.5A EP3684340A1 (fr) 2017-09-20 2018-09-11 Procédé de préparation d'une forme galénique solide comprenant des anticorps par granulation humide, extrusion et sphéronisation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17192259.4A EP3459527B1 (fr) 2017-09-20 2017-09-20 Procédé de préparation d'une forme posologique solide comprenant des anticorps par granulation par voie humide, extrusion et sphéronisation
EP17192259.4 2017-09-20

Publications (1)

Publication Number Publication Date
WO2019057563A1 true WO2019057563A1 (fr) 2019-03-28

Family

ID=59923357

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/074521 WO2019057563A1 (fr) 2017-09-20 2018-09-11 Procédé de préparation d'une forme galénique solide comprenant des anticorps par granulation humide, extrusion et sphéronisation

Country Status (11)

Country Link
US (1) US20200268675A1 (fr)
EP (2) EP3459527B1 (fr)
JP (1) JP7316268B2 (fr)
KR (1) KR20200054984A (fr)
CN (2) CN111107841B (fr)
AR (1) AR112701A1 (fr)
CA (1) CA3075875A1 (fr)
ES (1) ES2938608T3 (fr)
MX (1) MX2020003031A (fr)
TW (1) TWI799446B (fr)
WO (1) WO2019057563A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2020225202B2 (en) 2019-02-18 2023-10-26 Eli Lilly And Company Therapeutic antibody formulation
US20220192992A1 (en) * 2019-04-01 2022-06-23 Vta Labs, Llc Protection of monoclonal antibody integrity against evaporative solidification, compression and proteolysis by dextran and cyclodextrin derivatives
WO2020243393A1 (fr) * 2019-05-30 2020-12-03 Vta Labs, Llc Conception d'un système d'administration par voie orale unique contenant un anticorps monoclonal pour le traitement simultané de la maladie de crohn et de la colite ulcéreuse

Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2246570A (en) 1989-12-21 1992-02-05 Celltech Ltd Humanised antibodies
WO1992011383A1 (fr) 1990-12-21 1992-07-09 Celltech Limited ANTICORPS DE RECOMBINAISON SPECIFIQUE AU FNT-$g(a)
GB2297145A (en) 1995-01-23 1996-07-24 Western Atlas Int Inc EBW perforating gun system
US5919452A (en) 1991-03-18 1999-07-06 New York University Methods of treating TNFα-mediated disease using chimeric anti-TNF antibodies
EP0935523A1 (fr) 1996-10-28 1999-08-18 Inc. General Mills Inclusion et encapsulation de particules a liberation controlee
WO1999045903A1 (fr) * 1998-03-10 1999-09-16 Immucell Corporation Apport de compositions proteiques ou peptidiques dans le colon
WO2000024382A2 (fr) 1998-10-22 2000-05-04 Basf Aktiengesellschaft Procede pour produire des matieres solides spheriques, contenant une substance biologiquement active
EP1064935A1 (fr) 1999-06-28 2001-01-03 Adir Et Compagnie Composition pharmaceutique solide thermoformable à libération côntrolée
EP1083196A1 (fr) 1999-09-10 2001-03-14 Basf Aktiengesellschaft Granulation sous l'eau à l'état fondu comprenant un principe actif
WO2001076562A1 (fr) 2000-04-03 2001-10-18 Novasso Oy Formulation pharmaceutique administree par voie buccale assurant la liberation regulee d'un medicament
EP1166776A2 (fr) 2000-06-19 2002-01-02 Basf Aktiengesellschaft Procédé de préparation de formes orales solides à libération retardée
EP1171101A1 (fr) 1999-04-22 2002-01-16 Euroceltique S.A. Procede de realisation d'une matrice a action prolongee amorphe ou partiellement amorphe insoluble dans l'eau
GB2367002A (en) 2000-09-25 2002-03-27 British Sugar Plc Coating composition
WO2002035991A2 (fr) * 2000-10-30 2002-05-10 The Board Of Regents, The University Of Texas System Particules spheriques produites a l'aide d'un procede d'extrusion/spheronisation a chaud
WO2003068196A1 (fr) 2002-02-13 2003-08-21 Alizyme Therapeutics Limited Composition a liberation colique
WO2006131013A2 (fr) 2005-06-07 2006-12-14 Esbatech Ag Anticorps stables et solubles inhibant le tnfa
WO2007122374A2 (fr) 2006-04-13 2007-11-01 School Of Pharmacy, University Of London Préparation pour administration médicamenteuse colonique
EP1978940A2 (fr) 2006-01-19 2008-10-15 Dow Global Technologies Inc. Composition biologiquement active contenant de l'éthylcellulose
EP1996163A2 (fr) 2006-03-10 2008-12-03 Abbott GmbH & Co. KG Procédé de production d'une dispersion solide d'un principe actif
EP2066309A2 (fr) 2007-04-04 2009-06-10 Sigmoid Pharma Limited Composition pharmaceutique orale
WO2009155723A2 (fr) 2008-06-25 2009-12-30 Esbatech, An Alcon Biomedical Research Unit Llc ANTICORPS STABLES ET SOLUBLES INHIBANT LE TNFα
EP2144599A2 (fr) 2007-03-02 2010-01-20 Farnam Companies, Inc. Granules à libération prolongée utilisant des matières cireuses
WO2012130872A1 (fr) * 2011-03-28 2012-10-04 Ablynx Nv Procédé de production de formulations solides comprenant des domaines variables uniques d'immunoglobuline
US8293235B2 (en) 2008-06-25 2012-10-23 ESBATech, an Alcon Biomedical Research Unit, LLC Humanization of rabbit antibodies using a universal antibody framework
EP2512453A2 (fr) 2009-12-18 2012-10-24 Ferring B.V. Granulés pour préparations pharmaceutiques, procédés et appareil pour leur production
US8697074B2 (en) 2008-07-10 2014-04-15 Esbatech, An Alcon Biomedical Research Unit Llc Methods and compositions for enhanced delivery of macromolecules

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5286493A (en) * 1992-01-27 1994-02-15 Euroceltique, S.A. Stabilized controlled release formulations having acrylic polymer coating
KR20050110628A (ko) * 2003-02-10 2005-11-23 엘란 파마슈티칼스, 인크. 면역글로불린 제제 및 이의 제조방법
US8318230B2 (en) * 2005-05-02 2012-11-27 Henkel Ag & Co. Kgaa Use of debranched starch in extrusion-spheronization pharmaceutical pellets
CN101453996B (zh) * 2006-04-03 2016-05-11 伊萨·奥迪迪 药物递送组合物
MX354100B (es) * 2007-11-30 2018-02-13 Abbvie Biotechnology Ltd Star Formulaciones de proteinas y metodos para elaborarlas.
CA2734646C (fr) * 2008-08-20 2016-06-28 James W. Mcginity Extrusion a chaud de multiparticules a liberation modifiee
ES2572919T3 (es) * 2014-05-23 2016-06-03 Ares Trading S.A. Composición farmacéutica líquida
KR102294577B1 (ko) * 2015-01-12 2021-08-26 엔터리스 바이오파마, 인크. 고체 경구 제형
EP3435982A1 (fr) * 2016-03-31 2019-02-06 VHsquared Limited Compositions

Patent Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2246570A (en) 1989-12-21 1992-02-05 Celltech Ltd Humanised antibodies
WO1992011383A1 (fr) 1990-12-21 1992-07-09 Celltech Limited ANTICORPS DE RECOMBINAISON SPECIFIQUE AU FNT-$g(a)
US5919452A (en) 1991-03-18 1999-07-06 New York University Methods of treating TNFα-mediated disease using chimeric anti-TNF antibodies
GB2297145A (en) 1995-01-23 1996-07-24 Western Atlas Int Inc EBW perforating gun system
EP0935523A1 (fr) 1996-10-28 1999-08-18 Inc. General Mills Inclusion et encapsulation de particules a liberation controlee
WO1999045903A1 (fr) * 1998-03-10 1999-09-16 Immucell Corporation Apport de compositions proteiques ou peptidiques dans le colon
WO2000024382A2 (fr) 1998-10-22 2000-05-04 Basf Aktiengesellschaft Procede pour produire des matieres solides spheriques, contenant une substance biologiquement active
EP1171101A1 (fr) 1999-04-22 2002-01-16 Euroceltique S.A. Procede de realisation d'une matrice a action prolongee amorphe ou partiellement amorphe insoluble dans l'eau
EP1064935A1 (fr) 1999-06-28 2001-01-03 Adir Et Compagnie Composition pharmaceutique solide thermoformable à libération côntrolée
EP1083196A1 (fr) 1999-09-10 2001-03-14 Basf Aktiengesellschaft Granulation sous l'eau à l'état fondu comprenant un principe actif
WO2001076562A1 (fr) 2000-04-03 2001-10-18 Novasso Oy Formulation pharmaceutique administree par voie buccale assurant la liberation regulee d'un medicament
EP1166776A2 (fr) 2000-06-19 2002-01-02 Basf Aktiengesellschaft Procédé de préparation de formes orales solides à libération retardée
GB2367002A (en) 2000-09-25 2002-03-27 British Sugar Plc Coating composition
WO2002035991A2 (fr) * 2000-10-30 2002-05-10 The Board Of Regents, The University Of Texas System Particules spheriques produites a l'aide d'un procede d'extrusion/spheronisation a chaud
WO2003068196A1 (fr) 2002-02-13 2003-08-21 Alizyme Therapeutics Limited Composition a liberation colique
WO2006131013A2 (fr) 2005-06-07 2006-12-14 Esbatech Ag Anticorps stables et solubles inhibant le tnfa
EP2390267B1 (fr) 2005-06-07 2013-06-05 ESBATech - a Novartis Company LLC Anticorps stables et solubles inhibant le TNF (alpha)
EP1978940A2 (fr) 2006-01-19 2008-10-15 Dow Global Technologies Inc. Composition biologiquement active contenant de l'éthylcellulose
EP1996163A2 (fr) 2006-03-10 2008-12-03 Abbott GmbH & Co. KG Procédé de production d'une dispersion solide d'un principe actif
WO2007122374A2 (fr) 2006-04-13 2007-11-01 School Of Pharmacy, University Of London Préparation pour administration médicamenteuse colonique
EP2144599A2 (fr) 2007-03-02 2010-01-20 Farnam Companies, Inc. Granules à libération prolongée utilisant des matières cireuses
EP2066309A2 (fr) 2007-04-04 2009-06-10 Sigmoid Pharma Limited Composition pharmaceutique orale
WO2009155723A2 (fr) 2008-06-25 2009-12-30 Esbatech, An Alcon Biomedical Research Unit Llc ANTICORPS STABLES ET SOLUBLES INHIBANT LE TNFα
US8293235B2 (en) 2008-06-25 2012-10-23 ESBATech, an Alcon Biomedical Research Unit, LLC Humanization of rabbit antibodies using a universal antibody framework
US8673310B2 (en) 2008-06-25 2014-03-18 ESBA Tech, an Alcon Biomedical Research Unit LLC Stable and soluble antibodies inhibiting TNFα
US20140193400A1 (en) 2008-06-25 2014-07-10 ESBA Tech, an Alcon Biomedical Research Unit LLC Stable and soluble antibodies inhibiting tnf alpha
US8697074B2 (en) 2008-07-10 2014-04-15 Esbatech, An Alcon Biomedical Research Unit Llc Methods and compositions for enhanced delivery of macromolecules
EP2512453A2 (fr) 2009-12-18 2012-10-24 Ferring B.V. Granulés pour préparations pharmaceutiques, procédés et appareil pour leur production
WO2012130872A1 (fr) * 2011-03-28 2012-10-04 Ablynx Nv Procédé de production de formulations solides comprenant des domaines variables uniques d'immunoglobuline

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BANSAL ET AL., POLIM. MED., vol. 44, no. 2, 2014, pages 109 - 118
FENDLY ET AL., HYBRIDOMA, vol. 6, 1987, pages 359 - 370
MEAGER ET AL., HYBRIDOMA, vol. 6, 1987, pages 305 - 311
SAHOO ET AL., J PHARM RES OPIN, vol. 9, 2013, pages 65 - 68
STEPHENS ET AL., IMMUNOLOGY, vol. 85, 1995, pages 668 - 674
VARUM ET AL., INT. J. PHARM., vol. 395, no. 1-2, 2010, pages 26 - 36
VERMEER ET AL., BIOPHYS J., vol. 8, no. 1, 7 January 2000 (2000-01-07), pages 394 - 404
YADAV ET AL., INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 502, no. 1- 2, 2016, pages 181 - 187

Also Published As

Publication number Publication date
EP3459527A1 (fr) 2019-03-27
CN111107841B (zh) 2023-03-10
US20200268675A1 (en) 2020-08-27
TW201914576A (zh) 2019-04-16
JP7316268B2 (ja) 2023-07-27
CN111107841A (zh) 2020-05-05
CN116211832A (zh) 2023-06-06
CA3075875A1 (fr) 2019-03-28
ES2938608T3 (es) 2023-04-13
JP2020534287A (ja) 2020-11-26
EP3684340A1 (fr) 2020-07-29
TWI799446B (zh) 2023-04-21
KR20200054984A (ko) 2020-05-20
AR112701A1 (es) 2019-11-27
MX2020003031A (es) 2020-07-22
EP3459527B1 (fr) 2022-11-23

Similar Documents

Publication Publication Date Title
CN109152738B (zh) 组合物
US20240099980A1 (en) Preparation of solid dosage forms comprising antibodies by solutions/suspension layering
US20200268675A1 (en) Method for preparing a solid dosage form comprising antibodies by wet granulation, extrusion and spheronization
US20240000714A1 (en) Topical treatment of inflammatory bowel disease using antibodies and fragments thereof
EP3459529A1 (fr) Préparation de formes posologiques solides à libération prolongée comprenant des anticorps par séchage par pulvérisation
WO2017173068A1 (fr) Système microparticulaire pour l'administration de médicaments au niveau du côlon
JP2022533635A (ja) 安定剤としてジペプチドを含むタンパク質組成物
EA044207B1 (ru) Получение твердых лекарственных форм, содержащих антитела, путем наслаивания раствора суспензии

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18768882

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3075875

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2020515727

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018768882

Country of ref document: EP

Effective date: 20200420